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Kinases: The "Indispensables"of the DNA Damage Response Cascade

Vijay Menon(1), and M. Michael Dcona(2)

Author Information

1Department of Cell,Development and Regenerative Biology, Icahn School of  Medicine at Mount Sinai, New York, New York10029, USA

2Department ofInternal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA

#Correspondence: vijay.menon@mssm.edu

Citation Information
JoLS, Vol 1, No. 2, September 2019:11-25


The human genome is exposed to a gamut of cellular and exogenous insults on a daily basis which needs to be monitored for proper cellular functioning and survival. This surveillance is undertaken by a myriad of protein players that ensure temporal and spatial regulation of cellular homeostasis. Kinases lie at the epicenter of the DNA damage response and exhibit a dynamic functionality, from responding to the damage to regulating the role of other proteins involved in detecting and repairing the damage. Here, we review some of the key kinases involved in DNA damage response pathways and their inhibitors that are either in clinical trials or have received approval for disease treatment.

Keywords: kinases; DNA damage response and repair; kinase inhibitors


Cellular DNA is constantly damaged by a wide variety of intrinsic and extrinsic factors, some of which mainly include DNA replication-induced base mismatches, bulky DNA adducts and DNA double-strand breaks (DSBs) caused by UV and other forms of radiation, intrastrand and interstrandcrosslinks (ICLs) caused by chemicals and byproducts of metabolic processes etc. (1) (2). Of these, DSBs and ICLs form the most deleterious lesions since it involves both strands of DNA and affect the major DNA transactions like replication, recombination, and transcription, causing major cellular damage. The cellular machinery has a repertoire of different mechanisms to circumvent these insults, preferably by halting the cell cycle progression and allowing the cells to either repair the damage or undergo apoptosis. This is extremely critical for the maintenance of cellular homeostasis and genomic integrity.

The DNA damage response (DDR) is mediated by an intricate network of proteins that are recruited to sites of damaged DNA in a highly orchestrated and regulated fashion. The accumulation of these proteins is dictated by a wide range of post-translational modifications (PTMs) like ubiquitylation, sumoylation, phosphorylation, neddylation etc. occurring both within the chromatin and the incoming responders. Of these, phosphorylation is one of the crucial PTMs governing the regulation of DNA damage signaling events and in this context, protein kinases constitute an important class of signaling molecules that are often dysregulated or mutated in human cancers, making them ideal candidates for targeted therapy (3) (4). The significance of kinases in DDR pathways have been studied for decades using knockdown or overexpression studies. More recently, there has been an explosion of drug screening studies that have identified kinases as essential drug targets, thus underscoring their importance not only in DDR pathways (5) but in a wide variety of signal transduction pathways. In this review, we will focus on some of the important protein kinases encoded by the human genome that are primarily involved in the DDR pathways. We would like to note here that, some of these kinases have been extensively reviewed earlier (5-7) We will try to give a fresh perspective as to how these kinases are activated and the subsequent functions they elicit in response to DNA damage, although some information still remains the same. We will conclude with a brief insight into their potential for cancer therapeutic intervention, thus bolstering the cancer armamentarium.

Serine/Threonine Protein Kinases - (ATM, ATR, DNA-PK) and (Chk1, Chk2): The brotherhood of DDR kinases

The response to DNA damage in eukaryotic genomes is mediated through kinases that belong to the family of phosphoinositide 3-kinase (PI3K)-related kinases [PIKKSs (8)]. The three main kinases that are responsible for detecting and signaling DNA damage are ataxia telangiectasia mutated (ATM), ATM and RAD3-related (ATR), and DNA-dependent protein kinase (DNA-PK) (6) (7). Of these, ATM and DNA-PK specifically respond to DNA DSBs whereas ATR responds to DNA single-strand breaks. Here, we will describe briefly the structural similarities between the three kinases and their mechanism of activation and regulation.

ATM, ATR, and DNA-PK are large proteins and share structural similarities with respect to domain organization and other structural features. Of these, DNA-PK is a huge complex consisting of the Ku heterodimer and a catalytic subunit which is termed as DNA-PKcs (1)(9). These kinases comprise of a C-terminal kinase domain flanked by two focal adhesion kinase targeting (FAT) domains-FAT and FATC ("C" indicates carboxy terminus) (10). The N-terminus mainly consists of Huntingtin, elongation factor 3, protein phosphatase 2A, and target of rapamycin 1 (HEAT)-repeat domains that is responsible for protein-protein interactions (11). In addition to these, a PIKK regulatory domain (PRD) is also present between the kinase and FATC domains (Figure 1A). ATM, ATR and DNA-PK are serine-threonine kinases that can recognize serine/glutamine (SQ) or threonine/glutamine (TQ) motifs in various substrates and phosphorylate them (12-14). Importantly, these kinases also have multiple SQ/TQ motifs and as a result can autophoshorylate on activation (15-17).

The recruitment of these kinases to sites of DNA damage is facilitated by their interaction with specific co-activators, which mainly occur via the HEAT-repeat domains. Ku80, Nijmegen breakage syndrome protein (NBS1), and ATR-interacting protein (ATRIP) are the co-activators for DNA-PKcs, ATM, and ATR respectively (18-20). Following the formation of a DNA DSBs, ATM is recruited to these sites through its binding to Nbs1 (a part of the Mre11-Rad50-Nbs1 or MRN complex). The MRN complex activates ATM's kinase activity which then phosphorylates a cascade of different proteins downstream. ATM phosphorylates histone H2AX at Ser 139 which is then recognized by mediator of DNA damage checkpoint protein 1 (MDC1) and helps to sustain ATM activation in a feedforward loop. This initiates a ubiquitylation-dependent DDR response through the recruitment of ring finger protein 8 (RNF8) and ring finger protein RNF168 (RNF169) which further recruits p53-binding protein (53BP1) to these sites(21). In addition to the role of the MRN complex in ATM activation, another factor that also influences ATM activation is Histone Acetyl Transferase (KAT5) or Tip60 (22), which is recruited to sites of DNA damage and acetylates ATM at Lys 3016. A more recent study showed that UFM1 specific ligase 1 (UFL1), the E3 ligase that conjugates Ubiquitin-fold modifier 1 (UFM1) to its substrates, also called UFMylation, initiates a long signaling cascade wherein it UFMylates histone H4 which then recruits the suppressor of variegation 3-9 homolog 1 (Suv39h1) complex to DSBs. This then trimethylates histone H3 at Lys 9 leading to KAT5/Tip60 accumulation and subsequent ATM activation (23) (24). The importance of UFMylation in ATM activation was also shown in another study by Wang et al. (2019) where they showed that UFL1 UFMylates meiotic recombination 11 (MRE11) at Lys 282, leading to MRN complex formation and ATM activation (25). In the same context, Ha et al. (2019) showed that Pellino1, a ubiquitin ligase which responds to DNA DSBs, is involved in ATM activation through a phospho-H2AX-NBS1-ATM signaling axis (26). These studies show that the mechanisms behind ATM activation are still being deciphered and suggest an important link to a wide range of post-translational modifications.

The repair of these DNA DSBs is needed to allow proper survival of the cells. Some of the pathways that are involved in the repair of DNA DSBs are non-homologous end joining (NHEJ), homologous recombination repair (HRR), single-strand annealing (SSA), microhomology-mediated end joining (MMEJ) etc. Earlier studies have shown ATM to be involved in NHEJ and HRR pathways, although the exact mechanism is still not known.

Figure 1: Structural Organization of Serine/Threonine Protein Kinases. (A.) Domain structuresfor ATM/ATR/DNA-PKcs: HEAT, Huntington elongation factor 3; FAT, FRAP-ATM-TRRAP; kinase domain shown in red; FATC, FAT c-terminal. Co-activators are shown in purple. (B.) Domain structures for Checkpoint kinases, Chk1 and Chk2: SQ/TQ domain containing multiple ATM/ATR phosphorylation sites; FHA, forkhead-associated domain; kinase domain shown in red. Figures adapted from references (7), (8), and (38).

ATR, in contrast to ATM and DNA-PK, responds to a wide range of DNA damaging lesions. Of these, ssDNA formed in cells (through replication, transcription, or repair) is the primary structure that activates ATR. The ssDNA is then coated with replication protein A (RPA), which is then recognized by the ATRIP protein that helps in localizing the ATRIP-ATR complex to sites of replication stress and DNA damage (32). However, the kinase activity of ATR is triggered by its interaction, mediated by the Rad9-Hus1-Rad1 (9-1-1) complex, with DNA topoisomerase II-binding protein 1 (TopBP1) that contains an ATR-activation domain and is known to function in replication and checkpoint activation (33) (34). Ewing's tumor-associated antigen 1 (ETAA1) is another activator identified for ATR, which binds to RPA-coated ssDNA but does not require the 9-1-1 complex (35-37).

The DDR elicited by ATM/ATR leads to the G1, S, and G2 checkpoint activation primarily through activation of another set of serine/threonine kinases, checkpoint kinase 1 (Chk1) and (Chk2) (reviewed in (38)(Figure 1B). When the cells encounter a DNA DSB during the G1 phase, ATM phosphorylates p53 tumor suppressor protein at Ser 15 which was also shown to be a phosphorylation site for ATR in the absence of ATM (39) (40). Alternatively, ATM phosphorylates Chk2 at Thr68 which then phosphorylates p53 at Ser 20 (41) (42). These phosphorylation events on p53 then ultimately lead to G1 phase arrest or apoptosis. When the ionizing radiation (IR)-induced lesion is encountered during the S phase, the ATM/Chk2 pathway is activated and leads to the phosphorylation and degradation of cell division cycle 25A (Cdc25A) at Ser 123, a phosphatase that is required for activation of the cyclin-dependent kinase 2 (Cdk2)/cyclin A complex for DNA synthesis and subsequent S phase progression (43). A disruption in this pathway leads to a radioresistant DNA synthesis (RDS) phenotype. On the other hand, when the lesion encountered is through UV radiation or replication errors, ATR gets activated which then phosphorylates Chk1, BRCA1 or Nbs1 leading to S phase delay or replication fork restart. Finally, when the lesion encountered is during the S/G2 phase of the cell cycle, two possibilities occur. Cells in G1-S phase, following irradiation, activate ATR which then phosphorylates Chk1 at Ser 345 (44)and cells in G2 phase itself, following irradiation, activate ATM which then phosphorylates Chk2 at Thr68 (45) and both of these events ultimately cause cytoplasmic sequestration of Cdc25C phosphatase, preventing the activation of mitotic cyclin B.cdc2 complex.

In addition tothese kinases, there are other serine/threonine kinases that also get activated in response to DNA damaging agents. Since a detailed discussion of these kinases is beyond the scope of this review, we have summarized these kinases and their functions in DDR as listed in Table 1. In summary, the three DDR kinases, ATM, ATR and DNA-PK and the checkpoint kinases, Chk1 and Chk2 constitute the major serine/threonine kinases that form some of the pivotal building blocks of the DDR response, the absence of which can lead to catastrophic consequences within the genome leading to genomic instability and cancer.

Tyrosine Kinases: A major supporting cast in the DDR

Tyrosine kinases - both receptor (RTKs) and non-receptor (NRTKs) - regulate important cellular signaling events pertaining to proliferation, differentiation, survival etc.In the case of the DDR, tyrosine kinases are activated and interact with and regulate the activity of different proteins involved in the DDR, repair and cell cycle progression. Additionally, they epigenetically regulate DDR proteins through histone and chromatin modifications. In humans there are several subfamilies and groups of receptor and non-receptor tyrosine kinases (58) (59). We will briefly discuss a few examples from each group, especially focusing on their roles in DDR

Epidermal growth factor receptor (EGFR) is one of the transmembrane RTKs, mutations in which have been associated with many cancers. EGFR is phosphorylated at residues Y845 and Y1173 after irradiation and then interacts with DNA-PK (60). In this context, Zhou et al. showed that the insulin-like growth factor binding protein 2 (IGFPB2) activates EGFR-DNA-PKcs signaling and this prevents DNA damage induced by bile salts in esophageal adenocarcinoma, likely due to increased DNA repair through NHEJ (61). Extracellular-signal-regulated kinase (ERK) activation has been seen on DNA damage and a recent study demonstrated a biphasic activation of ERK with the first phase requiring EGFR and eventually activating pro-survival signals and the second phase requiring protein kinase C delta (PKCδ) to promote apoptosis (62). Apart from the DDR, many studies have also shown EGFR to be involved in DSB repair. For example, EGFR interacts with BRCA1 and also phosphorylates ATM at Tyr 370 upon DSB formation (63) (64). In summary, these studies show the duality of EGFR in regulating both the DDR and Repair. Other than EGFR, Insulin like Growth Factor 1 Receptor (IGF-1R) is another RTK that is also activated by ionizing radiation and has been shown to be involved in DNA repair by HR(65) (66). Another role was shown by Kemp et al. wherein IGF-1R is needed for the ATR-Chk1 signaling in human keratinocytes exposed to UV-B radiation (67). In neurons, the tropomyosin receptor kinase A (TrkA) is a RTK that is a receptor for neurotrophin that are needed for the development and function of neurons (68). It was seen that human SY5Y neuroblastoma cells showed increased NHEJ via upregulated XRCC4 which was attributed to overexpression of TrkA (69). Non-receptor tyrosine kinases (NRTKs) are cytosolic proteins and are capable of translocating into the nucleus to transmit signals from activated RTKs and activate DDR pathways. The Abelson murine leukemia viral oncogene homolog 1 (Abl-1) is a NRTK that is activated inresponse to genotoxic stress and phosphorylates different proteins involved in DNA repair and cell cycle checkpoints. A wide range of Abl-1 activity during DDR has been demonstrated over the past many years.

* NEK1 kinase has also been reported to be a dual-specificity kinase (48) ** CK2 has also been reported to be a dual specificity protein kinase (57)

Abl-1 interacts with Ku and dissociates the Ku-DNA-PKcs complex during NHEJ (70). In response to DNA damage, Abl-1 phosphorylates the homeodomain-interacting protein kinase 2 (HIPK2) at Tyr 360 and induces apoptosis(47). A unique function of Abl-1 in DDR was recently demonstrated in which Abl-1 activity was seen on RNA pol II following DNA damage to produce damage-responsive transcripts, an important component of RNA-dependent DDR (71). The Src family of NRTKs mainly constitutes Src, Lyn and Fyn kinases. Of these, Src has been shown to promote the termination of the DDR through silencing ATR-Chk1 signaling (72). Further, in response to ionizing radiation, Lyn kinase has been shown to regulate DNA-PK and also interact with CDK1 (73). These were some of the classical NRTKs and their distinct roles in the DDR. Before we conclude, it is noteworthy to mention about the Williams syndrome transcription factor (WSTF) kinase which is neither a RTK nor a NRTK, but a bona fide TK which quite recently was shown to phosphorylate H2AX at Tyr 142 and induces transcription-coupled HR at DNA breaks (74).

Dual Specificity Kinases: Let's also play in the DDR

Majority of the kinases involved in the DDR as discussed above are either serine/threonine kinases or tyrosine kinases. However, certain kinases are able to phosphorylate both serine/threonine and tyrosine residues on protein substrates and constitute the dual specificity kinases. The dual-specificity tyrosine-phosphorylation-regulated kinases (DYRKs) have been shown to regulate cell survival, protein stability, cell cycle control and apoptosis (75-77). ATM was shown to phosphorylate DYRK2, facilitating its nuclear entry and protection from mouse double minute 2 homology (MDM2)-mediated degradation (78). Recently, three independent studies showed the involvement of DYRK1A in the DNA damage response (79-81). To our knowledge, this is the first time a direct involvement of DYRK kinases in the DNA damage response has been shown. LIM kinases are another group of dual specificity kinases that control microtubule and actin dynamics. In the context of DDR, the only known role of LIM kinases was shown by the increased expression of the LIMK2b isoform which was regulated by p53. Further, deletion of LIMK2b resulted in impaired G2/M arrest following irradiation (82). Proliferating cells show high levels of TTK kinases which are human homologs of the yeast Monopolar spindle 1 (Mps1) and are dual specificity protein kinases (83). After irradiation, TTK/hMps1 ("h" for human) phosphorylates Chk2 at Thr68 and knockdown of TTK showed impaired G2/M arrest (84). TTK/hMps1 was also shown to phosphorylate MDM2 at Thr304 and Thr306 after H2O2-induced oxidative stress, suggesting a broad functionality of TTK in various forms of DNA damage (85).We believe that future phosphoproteomic studies could identify and help in characterizing many more dual specificity kinases that play important roles in the DNA damage response and, maybe, repair.

Kinase Inhibitors and Therapeutic Intervention:

Tyrosine kinases have been extensively investigated as therapeutic targets, especially in the context of cancer-therapy. A significant number of small molecules and antibodies continue to receive FDA approvals, while many more are in early/late stages of clinical-trials. Clinical studies are also expanding the application of these pharmacological entities toward treatment of other diseases such as inflammation, neurodegeneration, infectious diseases and auto-immune disorders (86). Additionally, evidence suggests that combination therapy with one entity targeting a kinase pathway significantly delays resistance and improves overall response (87). As a result, multiple clinical-trials have included a kinase targeting pharmacological entity in their approach (For e.g., NCT00672295, NCT03799094; https://clinicaltrials.gov/). Tyrosine kinase inhibitors (or TKIs) are a class of pharmacological molecules designed to inhibit the phosphorylation of tyrosine (Y) residues on proteins that play a key role in various cellular pathways. These molecules, especially small molecule inhibitors, compete with ATP for binding in the intracellular catalytic domains of tyrosine kinases that possess specific mutations or that are overexpressed in cancer cells which results in a constitutively active kinase. For e.g., Imatinib mesylate was one of the first kinase inhibitors that was approved for cancer treatment and it functions by occupying the active-site evicting ATP and thereby diminishing phosphorylation. As mentioned above, the kinases that participate in DDR are reported to be genetically altered frequently in a number of cancer subtypes. Therefore, these enzymes represent potential therapeutic targets in cancer therapy. Several reviews have already illustrated the application of clinically actionable inhibitors that target ATM, ATR or DNA-PK (88), (89). Multiple studies have investigated the effects of pharmacological inhibition of these enzymes in cohorts of animals and humans (90-92). In Table 2, we list the FDA approved drugs (small molecule inhibitors/mAbs) mainly for tyrosine kinases since clinical trials are still ongoing for Ser/Thr and Dual Specificity kinases. Additionally, we also list out common genetic alterations that are found in these kinases in every cancer-type, as per TCGA database (cbioportal.org) (99-100)

Conclusions and Future perspectives:

Cancer continues to be a leading cause of death worldwide, commonly due to acquired drug resistance and cancer metastasis. Although these two events are considered to be independent events, they are caused due to multiple kinases working in unison at a molecular level. While existing kinase inhibitors often fail to overcome the resistance offered by the diseases, new inhibitors that target “undruggable” kinases are highly desirable.

This is possible by comprehensive characterization of protein signaling pathways that are regulated by these kinases, which will be critical for the development of future curative therapies not only cancers but for many other diseases/disorders.

In light of this, protein kinases form the cornerstone of the DDR and primarily act as key regulators of a wide range of signal transduction pathways required to maintain cellular stability and survival. An in-depth knowledge of the crosstalks between these kinases before or after DNA damage would be immensely useful to study and identify potential driver mutations that lead to tumorigenesis via conferring a selective growth advantage to cancer cells and passenger mutations that do not confer any selective phenotype. Future studies should be focused on identifying more players that are specifically a part of the DDR, understanding their mechanism of action, and determining if they are suitable targets for different modes of treatment and cure.


1. T. Lindahl, D.E. Barnes, Repair of Endogenous DNA Damage, Cold Spring Harb. Symp. Quant. Biol. 65 (2000) 127–134. doi:10.1101/sqb.2000.65.127

2. J.F. Ward, DNA Damage Produced by Ionizing Radiation in Mammalian Cells: Identities, Mechanisms of Formation, and Reparability, Prog. Nucleic Acid Res. Mol. Biol. 35 (1988) 95–125. doi:10.1016/S0079-6603(08)60611-X.

3. P. Workman, Drugging the cancer kinome: Progress and challenges in developing personalized molecular cancer therapeutics, in: Cold Spring Harb. Symp. Quant. Biol., 2005: pp. 499–515. doi:10.1101/sqb.2005.70.020.

4. E.D.G. Fleuren, L. Zhang, J. Wu, R.J. Daly, The kinome “at large” in cancer, Nat. Rev. Cancer. 16 (2016) 83–98. doi:10.1038/nrc.2015.18.

5. M. Owusu, P. Bannauer, J. Ferreira da Silva, T.P. Mourikis, A. Jones, P. Májek, M. Caldera, M. Wiedner, C.-H. Lardeau, A.C. Mueller, J. Menche, S. Kubicek, F.D. Ciccarelli, J.I. Loizou, Mapping the Human Kinome in Response to DNA Damage., Cell Rep. 26 (2019) 555-563.e6. doi:10.1016/j.celrep.2018.12.087.

6. A.N. Blackford, S.P. Jackson, ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response, Mol. Cell. 66 (2017) 801–817. doi:10.1016/j.molcel.2017.05.015.

7. A. Maréchal, L. Zou, DNA damage sensing by the ATM and ATR kinases., Cold Spring Harb. Perspect. Biol. 5 (2013). doi:10.1101/cshperspect.a012716.

8. C.A. Lovejoy, D. Cortez, Common mechanisms of PIKK regulation, DNA Repair (Amst). 8 (2009) 1004–1008. doi:10.1016/j.dnarep.2009.04.006.

9. G.C.M. Smith, S.P. Jackson, The DNA-dependent protein kinase, Genes Dev. 13 (1999) 916–934. doi:10.1101/gad.13.8.916

10. R. Bosotti, A. Isacchi, E.L.L. Sonnhammer, FAT: A novel domain in PIK-related kinases, Trends Biochem. Sci. 25 (2000) 225–227. doi:10.1016/S0968-0004(00)01563-2.

11. J. Perry, N. Kleckner, The ATRs, ATMs, and TORs are giant HEAT repeat proteins, Cell. 112 (2003) 151–155. doi:10.1016/S0092-8674(03)00033-3.

12. S.T. Kim, D.S. Lim, C.E. Canman, M.B. Kastan, Substrate specificities and identification of putative substrates of ATM kinase family members, J. Biol. Chem. 274 (1999) 37538–37543. doi:10.1074/jbc.274.53.37538.

13. S.P. Lees-Miller, C.W. Anderson, The human double-stranded DNA-activated protein kinase phosphorylates the 90-kDa heat-shock protein, hsp90?? at two NH2-terminal threonine residues, J. Biol. Chem. 264 (1989) 17275–17280.

14. . O’Neill, A.J. Dwyer, Y. Ziv, D.W. Chan, S.P. Lees-Miller, R.H. Abraham, J.H. Lai, D. Hill, Y. Shiloh, L.C. Cantley, G.A. Rathbun, Utilization of oriented peptide libraries to identify substrate motifs selected by ATM, J. Biol. Chem. 275 (2000) 22719–22727. doi:10.1074/jbc.M001002200.

15. N. Uematsu, E. Weterings, K.I. Yano, K. Morotomi-Yano, B. Jakob, G. Taucher-Scholz, P.O. Mari, D.C. Van Gent, B.P.C. Chen, D.J. Chen, Autophosphorylation of DNA-PKCS regulates its dynamics at DNA double-strand breaks, J. Cell Biol. 177 (2007) 219–229. doi:10.1083/jcb.200608077. 

16. C.J. Bakkenist, M.B. Kastan, DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation., Nature. 421 (2003) 499–506. doi:10.1038/nature01368.

17. S. Liu, B. Shiotani, M. Lahiri, A. Maréchal, A. Tse, C.C.Y. Leung, J.N.M. Glover, X.H. Yang, L. Zou, ATR Autophosphorylation as a Molecular Switch for Checkpoint Activation, Mol. Cell. 43 (2011) 192–202. doi:10.1016/j.molcel.2011.06.019.

18. B.K. Singleton, M.I. Torres-Arzayus, S.T. Rottinghaus, G.E. Taccioli, P.A. Jeggo, The C Terminus of Ku80 Activates the DNA-Dependent Protein Kinase Catalytic Subunit, Mol. Cell. Biol. 19 (2015) 3267–3277. doi:10.1128/mcb.19.5.3267

19. S. Difilippantonio, A. Celeste, O. Fernandez-Capetillo, H.T. Chen, B.R. San Martin, F. Van Laethem, Y.P. Yang, G. V. Petukhova, M. Eckhaus, L. Feigenbaum, K. Manova, M. Kruhlak, R.D. Camerini-Otero, S. Sharan, M. Nussenzweig, A. Nussenzweig, Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models, Nat. Cell Biol. 7 (2005) 675–685. doi:10.1038/ncb1270.

20. H.L. Ball, D. Cortez, ATRIP oligomerization is required for ATR-dependent checkpoint signaling, J. Biol. Chem. 280 (2005) 31390–31396. doi:10.1074/jbc.M504961200

21. C. Doil, N. Mailand, S. Bekker-Jensen, P. Menard, D.H. Larsen, R. Pepperkok, J. Ellenberg, S. Panier, D. Durocher, J. Bartek, J. Lukas, C. Lukas, RNF168 Binds and Amplifies Ubiquitin Conjugates on Damaged Chromosomes to Allow Accumulation of Repair Proteins, Cell. 136 (2009) 435–446. doi:10.1016/j.cell.2008.12.041.

22. M.K. Ayrapetov, O. Gursoy-Yuzugullu, C. Xu, Y. Xu, B.D. Price, DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin, Proc. Natl. Acad. Sci. 111 (2014) 9169–9174. doi:10.1073/pnas.1403565111.

23. B. Qin, J. Yu, S. Nowsheen, M. Wang, X. Tu, T. Liu, H. Li, L. Wang, Z. Lou, UFL1 promotes histone H4 ufmylation and ATM activation, Nat. Commun. 10 (2019). doi:10.1038/s41467-019-09175-0.

24. K. Tatsumi, Y.S. Sou, N. Tada, E. Nakamura, S.I. Iemura, T. Natsume, S.H. Kang, C.H. Chung, M. Kasahara, E. Kominami, M. Yamamoto, K. Tanaka, M. Komatsu, A novel type of E3 ligase for the Ufm1 conjugation system, J. Biol. Chem. 285 (2010) 5417–5427. doi:10.1074/jbc.M109.036814.

25. Z. Wang, Y. Gong, B. Peng, R. Shi, D. Fan, H. Zhao, M. Zhu, H. Zhang, Z. Lou, J. Zhou, W.-G. Zhu, Y.-S. Cong, X. Xu, MRE11 UFMylation promotes ATM activation, Nucleic Acids Res. (2019). doi:10.1093/nar/gkz110.

26. G.H. Ha, J.H. Ji, S. Chae, J. Park, S. Kim, J.K. Lee, Y. Kim, S. Min, J.M. Park, T.H. Kang, H. Lee, H. Cho, C.W. Lee, Pellino1 regulates reversible ATM activation via NBS1 ubiquitination at DNA double-strand breaks, Nat. Commun. 10 (2019). doi:10.1038/s41467-019-09641-9.

27. P.-O. Mari, B.I. Florea, S.P. Persengiev, N.S. Verkaik, H.T. Bruggenwirth, M. Modesti, G. Giglia-Mari, K. Bezstarosti, J.A.A. Demmers, T.M. Luider, A.B. Houtsmuller, D.C. van Gent, Dynamic assembly of end-joining complexes requires interaction between Ku70/80 and XRCC4, Proc. Natl. Acad. Sci. 103 (2006) 18597–18602. doi:10.1073/pnas.0609061103.

28. J.R. Walker, R.A. Corpina, J. Goldberg, Structure of the Ku heterodimer bound to dna and its implications for double-strand break repair, Nature. 412 (2001) 607–614. doi:10.1038/35088000.

29. A.A. Goodarzi, Y. Yu, E. Riballo, P. Douglas, S.A. Walker, R. Ye, C. Härer, C. Marchetti, N. Morrice, P.A. Jeggo, S.P. Lees-Miller, DNA-PK autophosphorylation facilitates Artemis endonuclease activity, EMBO J. 25 (2006) 3880–3889. doi:10.1038/sj.emboj.7601255.

30. S. Mohapatra, M. Kawahara, I.S. Khan, S.M. Yannone, L.F. Povirk, Restoration of G1 chemo/radioresistance and double-strand-break repair proficiency by wild-type but not endonuclease-deficient Artemis, Nucleic Acids Res. 39 (2011) 6500–6510. doi:10.1093/nar/gkr257.

31. Y. Zhou, J.H. Lee, W. Jiang, J.L. Crowe, S. Zha, T.T. Paull, Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM, Mol. Cell. 65 (2017) 91–104. doi:10.1016/j.molcel.2016.11.004.

32. L. Zou, S.J. Elledge, Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes, Science (80-. ). 300 (2003) 1542–1548. doi:10.1126/science.1083430.

33. J. Lee, A. Kumagai, W.G. Dunphy, The Rad9-Hus1-Rad1 checkpoint clamp regulates interaction of TopBP1 with ATR, J. Biol. Chem. 282 (2007) 28036–28044. doi:10.1074/jbc.M704635200

34. S. Delacroix, J.M. Wagner, M. Kobayashi, K.I. Yamamoto, L.M. Karnitz, The Rad9-Hus1-Rad1 (9-1-1) clamp activates checkpoint signaling via TopBP1, Genes Dev. 21 (2007) 1472–1477. doi:10.1101/gad.1547007.

35. P. Haahr, S. Hoffmann, M.A.X. Tollenaere, T. Ho, L.I. Toledo, M. Mann, S. Bekker-Jensen, M. Räschle, N. Mailand, Activation of the ATR kinase by the RPA-binding protein ETAA1, Nat. Cell Biol. 18 (2016) 1196–1207. doi:10.1038/ncb3422

36. Y.C. Lee, Q. Zhou, J. Chen, J. Yuan, RPA-Binding Protein ETAA1 Is an ATR Activator Involved in DNA Replication Stress Response, Curr. Biol. 26 (2016) 3257–3268. doi:10.1016/j.cub.2016.10.030.

37. S. Feng, Y. Zhao, Y. Xu, S. Ning, W. Huo, M. Hou, G. Gao, J. Ji, R. Guo, D. Xu, Ewing tumor-associated antigen 1 interacts with replication protein A to promote restart of stalled replication forks, J. Biol. Chem. 291 (2016) 21956–21962. doi:10.1074/jbc.C116.747758.

38. J. Bartek, J. Lukas, Chk1 and Chk2 kinases in checkpoint control and cancer, Cancer Cell. 3 (2003) 421–429. doi:10.1016/S1535-6108(03)00110-7.

39. S. Banin, L. Moyal, S.Y. Shieh, Y. Taya, C.W. Anderson, L. Chessa, N.I. Smorodinsky, C. Prives, Y. Reiss, Y. Shiloh, Y. Ziv, Enhanced phosphorylation of p53 by ATM in response to DNA damage, Science (80-. ). 281 (1998) 1674–1677. doi:10.1126/science.281.5383.1674.

40. N.D. Lakin, B.C. Hann, S.P. Jackson, The ataxia-telangiectasia related protein ATR mediates DNA-dependent phosphorylation of p53, Oncogene. 18 (1999) 3989–3995. doi:10.1038/sj.onc.1202973.

41. J.Y. Ahn, J.K. Schwarz, H. Piwnica-Worms, C.E. Canman, Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation, Cancer Res. 60 (2000) 5934–5936.

42. Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, et al, DNA damage-induced activation of p53 by the checkpoint kinase Chk2., Science (80-. ). 287 (2000) 1824–7.

43. J. Falck, N. Mailand, R.G. Syljuåsen, J. Bartek, J. Lukas, The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis, Nature. 410 (2001) 842–847. doi:10.1038/35071124.

44. Q. Liu, S. Guntuku, X.S. Cui, S. Matsuoka, D. Cortez, K. Tamai, G. Luo, S. Carattini-Rivera, F. DeMayo, A. Bradley, L.A. Donehower, S.J. Elledge, Chk1 is an essential kinase that is regulated by Atr and required for the G2/M DNA damage checkpoint, Genes Dev. 14 (2000) 1448–1459.

45. A.L. Brown, C.-H. Lee, J.K. Schwarz, N. Mitiku, H. Piwnica-Worms, J.H. Chung, A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage, Proc. Natl. Acad. Sci. 96 (2002) 3745–3750. doi:10.1073/pnas.96.7.3745.

46. I. Dauth, J. Krüger, T.G. Hofmann, Homeodomain-interacting protein kinase 2 is the ionizing radiation-activated p53 serine 46 kinase and is regulated by ATM, Cancer Res. 67 (2007) 2274–2279. doi:10.1158/0008-5472.CAN-06-2884.

47. N. Reuven, J. Adler, Z. Porat, T. Polonio-Vallon, T.G. Hofmann, Y. Shaul, The tyrosine kinase c-Abl promotes HIPK2 accumulation and activation in response to DNA damage, J. Biol. Chem. 290 (2015) jbc.M114.628982. doi:10.1074/jbc.M114.628982.

48. Y. Chen, C.F. Chen, D.J. Riley, P.L. Chen, Nek1 kinase functions in DNA damage response and checkpoint control through a pathway independent of ATM and ATR, Cell Cycle. 10 (2011) 655–663. doi:10.4161/cc.10.4.14814.

49. R. Polci, A. Peng, P.L. Chen, D.J. Riley, Y. Chen, NIMA-related protein kinase 1 is involved early in the ionizing radiation-induced DNA damage response, Cancer Res. 64 (2004) 8800–8803. doi:10.1158/0008-5472.CAN-04-2243.

50. X. Chen, H. Zhu, M. Yuan, J. Fu, Y. Zhou, L. Ma, G-protein-coupled receptor kinase 5 phosphorylates p53 and inhibits DNA damage-induced apoptosis, J. Biol. Chem. 285 (2010) 12823–12830. doi:10.1074/jbc.M109.094243

51. S. Zirkin, A. Davidovich, J. Don, The PIM-2 kinase is an essential component of the ultraviolet damage response that acts upstream to E2F-1 and ATM, J. Biol. Chem. 288 (2013) 21770–21783. doi:10.1074/jbc.M113.458851.

52. J. Ramachandran, L. Santo, K.T. Siu, C. Panaroni, N. Raje, Pim2 is important for regulating DNA damage response in multiple myeloma cells, Blood Cancer J. 6 (2016) e462. doi:10.1038/bcj.2016.73.

53. L. Herhaus, A.B. Perez-Oliva, G. Cozza, R. Gourlay, S. Weidlich, D.G. Campbell, L.A. Pinna, G.P. Sapkota, Casein kinase 2 (CK2) phosphorylates the deubiquitylase OTUB1 at Ser16 to trigger its nuclear localization, Sci. Signal. 8 (2015). doi:10.1126/scisignal.aaa0441.

54. J.R. Chapman, S.P. Jackson, Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage, EMBO Rep. 9 (2008) 795–801. doi:10.1038/embor.2008.103.

55. J. Roig, J.A. Traugh, p21-activated protein kinase γ-PAK is activated by ionizing radiation and other DNA-damaging agents. Similarities and differences to α-PAK, J. Biol. Chem. 274 (1999) 31119–31122. doi:10.1074/jbc.274.44.31119.

56. Y. Fang, T. Liu, X. Wang, Y.M. Yang, H. Deng, J. Kunicki, F. Traganos, Z. Darzynkiewicz, L. Lu, W. Dai, BubR1 is involved in regulation of DNA damage responses, Oncogene. 25 (2006) 3598–3605. doi:10.1038/sj.onc.1209392.

57. O. Marin, F. Meggio, S. Sarno, L. Cesaro, M.A. Pagano, L.A. Pinna, Tyrosine Versus Serine/Threonine Phosphorylation by Protein Kinase Casein Kinase-2 , J. Biol. Chem. 274 (2002) 29260–29265. doi:10.1074/jbc.274.41.29260.

58. G. Manning, D.B. Whyte, R. Martinez, T. Hunter, S. Sudarsanam, The protein kinase complement of the human genome, Science (80-. ). 298 (2002) 1912–1934. doi:10.1126/science.1075762.

59. S.R. Hubbard, J.H. Till, Protein Tyrosine Kinase Structure and Function, Annu. Rev. Biochem. 69 (2000) 373–398. doi:10.1146/annurev.biochem.69.1.373.

60. K. Dittmann, C. Mayer, R. Kehlbach, H.P. Rodemann, Radiation-induced caveolin-1 associated EGFR internalization is linked with nuclear EGFR transport and activation of DNA-PK, Mol. Cancer. 7 (2008). doi:10.1186/1476-4598-7-69.

61. Z. Zhou, H. Lu, S. Zhu, A. Gomaa, Z. Chen, J. Yan, K. Washington, W. El-Rifai, C. Dang, D. Peng, Activation of EGFR-DNA-PKcs pathway by IGFBP2 protects esophageal adenocarcinoma cells from acidic bile salts-induced DNA damage, J. Exp. Clin. Cancer Res. 38 (2019). doi:10.1186/s13046-018-1021-y.

62. A.M. Ohm, T. Affandi, M.E. Reyland, EGF receptor and PKC kinase activate DNA damage–induced pro-survival and pro-apoptotic signaling via biphasic activation of ERK and MSK1 kinases, J. Biol. Chem. 294 (2019) 4488–4497. doi:10.1074/jbc.RA118.006944.

63. S. Nowsheen, T. Cooper, J.A. Stanley, E.S. Yang, Synthetic Lethal Interactions between EGFR and PARP Inhibition in Human Triple Negative Breast Cancer Cells, PLoS One. 7 (2012). doi:10.1371/journal.pone.0046614.

64. H.J. Lee, L. Lan, G. Peng, W.C. Chang, M.C. Hsu, Y.N. Wang, C.C. Cheng, L. Wei, S. Nakajima, S.S. Chang, H.W. Liao, C.H. Chen, M. Lavin, K.K. Ang, S.Y. Lin, M.C. Hung, Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response, Cell Res. 25 (2015) 225–236. doi:10.1038/cr.2015.8.

65. J. Trojanek, T. Ho, L. Del Valle, M. Nowicki, J.Y. Wang, A. Lassak, F. Peruzzi, K. Khalili, T. Skorski, K. Reiss, Role of the insulin-like growth factor I/insulin receptor substrate 1 axis in Rad51 trafficking and DNA repair by homologous recombination., Mol. Cell. Biol. 23 (2003) 7510–24. http://www.ncbi.nlm.nih.gov/pubmed/14559999%0Ahttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC207618.

66. S. Yang, J. Chintapalli, L. Sodagum, S. Baskin, A. Malhotra, K. Reiss, L.G. Meggs, Activated IGF-1R inhibits hyperglycemia-induced DNA damage and promotes DNA repair by homologous recombination, Am. J. Physiol. Physiol. 289 (2005) F1144–F1152. doi:10.1152/ajprenal.00094.2005.

67. M.G. Kemp, D.F. Spandau, R. Simman, J.B. Travers, Insulin-like Growth Factor 1 Receptor Signaling Is Required for Optimal ATR-CHK1 Kinase Signaling in Ultraviolet B (UVB)-irradiated Human Keratinocytes., J. Biol. Chem. 292 (2017) 1231–1239. doi:10.1074/jbc.M116.765883.

68. M. Bibel, Y.A. Barde, Neurotrophins: Key regulators of cell fate and cell shape in the vertebrate nervous system, Genes Dev. 14 (2000) 2919–2937. doi:10.1101/gad.841400.

69. J.H. Schulte, S. Kuhfittig-Kulle, L. Klein-Hitpass, A. Schramm, D.S.F. Biard, P. Pfeiffer, A. Eggert, Expression of the TrkA or TrkB receptor tyrosine kinase alters the double-strand break (DSB) repair capacity of SY5Y neuroblastoma cells, DNA Repair (Amst). 7 (2008) 1757–1764. doi:10.1016/j.dnarep.2008.07.004.

70. S. Jin, S. Kharbanda, B. Mayer, D. Kufe, D.T. Weaver, Binding of Ku and c-Abl at the kinase homology region of DNA-dependent protein kinase catalytic subunit, J. Biol. Chem. 272 (1997) 24763–24766. doi:10.1074/jbc.272.40.24763.

71. K. Burger, M. Schlackow, M. Gullerova, Tyrosine kinase c-Abl couples RNA polymerase II transcription to DNA double-strand breaks, Nucleic Acids Res. 47 (2019) 3467–3484. doi:10.1093/nar/gkz024.

72. Y. Fukumoto, M. Morii, T. Miura, S. Kubota, K. Ishibashi, T. Honda, A. Okamoto, N. Yamaguchi, A. Iwama, Y. Nakayama, N. Yamaguchi, Src family kinases promote silencing of atr-chk1 signaling in termination of DNA damage checkpoint, J. Biol. Chem. 289 (2014) 12313–12329. doi:10.1074/jbc.M113.533752.

73. S. Kumar, P. Pandey, A. Bharti, S. Jin, R. Weichselbaum, D. Weaver, D. Kufe, S. Kharbanda, Regulation of DNA-dependent protein kinase by the Lyn tyrosine kinase, J. Biol. Chem. 273 (1998) 25654–25658. doi:10.1074/jbc.273.40.25654.

74. J.-H. Ji, S. Min, S. Chae, G.-H. Ha, Y. Kim, Y.-J. Park, C.-W. Lee, H. Cho, De novo phosphorylation of H2AX by WSTF regulates transcription-coupled homologous recombination repair., Nucleic Acids Res. (2019). doi:10.1093/nar/gkz309.

75. W. Becker, Emerging role of DYRK family protein kinases as regulators of protein stability in cell cycle control, Cell Cycle. 11 (2012) 3389–3394. doi:10.4161/cc.21404.

76. N. Taira, K. Nihira, T. Yamaguchi, Y. Miki, K. Yoshida, DYRK2 Is Targeted to the Nucleus and Controls p53 via Ser46 Phosphorylation in the Apoptotic Response to DNA Damage, Mol. Cell. 25 (2007) 725–738. doi:10.1016/j.molcel.2007.02.007.

77. L. Litovchick, L.A. Florens, S.K. Swanson, M.P. Washburn, J.A. Decaprio, DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly, Genes Dev. 25 (2011) 801–813. doi:10.1101/gad.2034211.

78. N. Taira, H. Yamamoto, T. Yamaguchi, Y. Miki, K. Yoshida, ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage, J. Biol. Chem. 285 (2010) 4909–4919. doi:10.1074/jbc.M109.042341.

79. V. R. Menon, V. Ananthapadmanabhan, S. Swanson, S. Saini, F. Sesay, V. Yakovlev, L. Florens, J.A. DeCaprio, M. P. Washburn, M. Dozmorov, L. Litovchick, DYRK1A regulates the recruitment of 53BP1 to the sites of DNA damage in part through interaction with RNF169, Cell Cycle. 18 (2019) 531–551. doi:10.1080/15384101.2019.1577525.

80. J. Roewenstrunk, C. Di Vona, J. Chen, E. Borras, C. Dong, K. Arató, E. Sabidó, M.S.Y. Huen, S. de la Luna, A comprehensive proteomics-based interaction screen that links DYRK1A to RNF169 and to the DNA damage response, Sci. Rep. 9 (2019). doi:10.1038/s41598-019-42445-x.

81. S.E. Guard, Z.C. Poss, C.C. Ebmeier, M. Pagratis, H. Simpson, D.J. Taatjes, W.M. Old, The nuclear interactome of DYRK1A reveals a functional role in DNA damage repair, Sci. Rep. 9 (2019) 6539. doi:10.1038/s41598-019-42990-5.

82. F.F. Hsu, T.Y. Lin, J.Y. Chen, S.Y. Shieh, P53-Mediated transactivation of LIMK2b links actin dynamics to cell cycle checkpoint control, Oncogene. 29 (2010) 2864–2876. doi:10.1038/onc.2010.40.

83. G.B. Mills, R. Schmandt, M. McGill, A. Amendola, M. Hill, K. Jacobs, C. May, A.M. Rodricks, S. Campbell, D. Hogg, Expression of TTK, a novel human protein kinase, is associated with cell proliferation, J. Biol. Chem. 267 (1992) 16000–16006.

84. J.H. Wei, Y.F. Chou, Y.H. Ou, Y.H. Yeh, S.W. Tyan, T.P. Sun, C.Y. Shen, S.Y. Shieh, TTK/hMps1 participates in the regulation of DNA damage checkpoint response by phosphorylating CHK2 on threonine 68, J. Biol. Chem. 280 (2005) 7748–7757. doi:10.1074/jbc.M410152200.

85. Z.C. Yu, Y.F. Huang, S.Y. Shieh, Requirement for human mps1/TTK in oxidative DNA damage repair and cell survival through MDM2 phosphorylation, Nucleic Acids Res. 44 (2016) 1133–1150. doi:10.1093/nar/gkv1173.

86. D. Hernández-Flórez, L. Valor, Protein-kinase Inhibitors: A New Treatment Pathway for Autoimmune and Inflammatory Diseases?, Reumatol. Clínica (English Ed. (2016). doi:10.1016/j.reumae.2015.06.003.

87. J.E. Dancey, H.X. Chen, Strategies for optimizing combinations of molecularly targeted anticancer agents, Nat. Rev. Drug Discov. (2006). doi:10.1038/nrd2089.

88. A. Minchom, C. Aversa, J. Lopez, Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies, Ther. Adv. Med. Oncol. 10 (2018). doi:10.1177/1758835918786658.

89. D. Velic, A.M. Couturier, M.T. Ferreira, A. Rodrigue, G.G. Poirier, F. Fleury, J.Y. Masson, DNA damage signalling and repair inhibitors: The long-sought-after achilles’ heel of cancer, Biomolecules. 5 (2015) 3204–3259. doi:10.3390/biom5043204.

90. M.E.M. Noble, J.A. Endicott, L.N. Johnson, Protein Kinase Inhibitors: Insights into Drug Design from Structure, Science (80-. ). (2004). doi:10.1126/science.1095920.

91. K. Takeuchi, F. Ito, Receptor Tyrosine Kinases and Targeted Cancer Therapeutics, Biol. Pharm. Bull. (2011). doi:10.1248/bpb.34.1774.

92. T. Helleday, E. Petermann, C. Lundin, B. Hodgson, R.A. Sharma, DNA repair pathways as targets for cancer therapy, Nat. Rev. Cancer. (2008). doi:10.1038/nrc2342.

93. D. Singh, B. Attri, R. Gill, J. Bariwal, Review On EGFR Inhibitors: Critical Updates, Mini-Reviews Med. Chem. 16 (2016) 1–1. doi:10.2174/1389557516666160804162457.

94. C.M. Lovly, N.T. McDonald, H. Chen, S. Ortiz-Cuaran, L.C. Heukamp, Y. Yan, A. Florin, L. Ozretić, D. Lim, L. Wang, Z. Chen, X. Chen, P. Lu, P.K. Paik, R. Shen, H. Jin, R. Buettner, S. Ansén, S. Perner, M. Brockmann, M. Bos, J. Wolf, M. Gardizi, G.M. Wright, B. Solomon, P.A. Russell, T.M. Rogers, Y. Suehara, M. Red-Brewer, R. Tieu, E. De Stanchina, Q. Wang, Z. Zhao, D.H. Johnson, L. Horn, K.K. Wong, R.K. Thomas, M. Ladanyi, W. Pao, Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer, Nat. Med. 20 (2014) 1027–1034. doi:10.1038/nm.3667.

95. A. Drilon, T.W. Laetsch, S. Kummar, S.G. DuBois, U.N. Lassen, G.D. Demetri, M. Nathenson, R.C. Doebele, A.F. Farago, A.S. Pappo, B. Turpin, A. Dowlati, M.S. Brose, L. Mascarenhas, N. Federman, J. Berlin, W.S. El-Deiry, C. Baik, J. Deeken, V. Boni, R. Nagasubramanian, M. Taylor, E.R. Rudzinski, F. Meric-Bernstam, D.P.S. Sohal, P.C. Ma, L.E. Raez, J.F. Hechtman, R. Benayed, M. Ladanyi, B.B. Tuch, K. Ebata, S. Cruickshank, N.C. Ku, M.C. Cox, D.S. Hawkins, D.S. Hong, D.M. Hyman, Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children , N. Engl. J. Med. 378 (2018) 731–739. doi:10.1056/nejmoa1714448.

96. M.D. Moen, K. McKeage, G.L. Plosker, M.A.A. Siddiqui, Imatinib: A review of its use in chronic myeloid leukaemia, Drugs. 67 (2007) 299–320. doi:10.2165/00003495-200767020-00010.

97. L.N. Puls, M. Eadens, W. Messersmith, Current Status of Src Inhibitors in Solid Tumor Malignancies, Oncologist. 16 (2011) 566–578. doi:10.1634/theoncologist.2010-0408.

98. H.-J. Nam, S.-A. Im, D.-Y. Oh, P. Elvin, H.-P. Kim, Y.-K. Yoon, A. Min, S.-H. Song, S.-W. Han, T.-Y. Kim, Y.-J. Bang, Antitumor activity of saracatinib (AZD0530), a c-Src/Abl kinase inhibitor, alone or in combination with chemotherapeutic agents in gastric cancer., Mol. Cancer Ther. 12 (2013) 16–26. doi:10.1158/1535-7163.MCT-12-0109.

99. N. Göckler, G. Jofre, C. Papadopoulos, U. Soppa, F.J. Tejedor, W. Becker, Harmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation, FEBS J. 276 (2009) 6324–6337. doi:10.1111/j.1742-4658.2009.07346.x.

100. F. Manetti, Recent advances in the rational design and development of LIM kinase inhibitors are not enough to enter clinical trials, Eur. J. Med. Chem. 155 (2018) 445–458. doi:10.1016/j.ejmech.2018.06.016.