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Our Science

Healthy cells have mechanisms, collectively known as the DNA damage response (DDR), to detect and repair DNA damage or induce cell death if the damage cannot be fixed.1

Many cancers have defects in DDR proteins and pathways that may render cells more susceptible to DNA damage.2

In cancer cells, inhibitors of the DDR have the potential to prevent DNA repair or maximize the DNA damage caused by anticancer therapies, ultimately resulting in cancer cell death. Additionally, in tumors that have acquired mutations in 1 or more DDR pathways, rendering them nonfunctional, inhibition of the remaining DDR pathway(s) could be fatal to cancer cells.1-4

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What Is the DNA Damage Response (DDR)?

The DDR is a complex surveillance and signaling network that has evolved to maintain genomic integrity. The DDR has 4 key functions1,4,5 :

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A plethora of proteins are involved in the DDR, but 3 serine/threonine protein kinases in particular have been identified as playing important roles across several DDR pathways: ATR, ATM, and DNA-PK.1,5

Ataxia telangiectasia and Rad3-related (ATR) protein kinase serves as a major regulator of the replication stress response. Replication stress leads to the generation of exposed sections of single-stranded DNA, which activates ATR kinase and leads to cell cycle arrest.1

Ataxia telangiectasia mutated (ATM) protein kinase is a master regulator of the response to DNA double-strand breaks (DSBs). ATM is activated in response to DNA DSBs and serves to induce cell cycle arrest and promote DNA damage repair.1,4,6

DNA-dependent protein kinase (DNA-PK) is involved in the repair of DSBs via nonhomologous end joining (NHEJ). This process is required for maintaining the integrity of the genome in healthy cells, but it also contributes to the survival of cancer cells exposed to DSB-inducing therapies.7,8

 

Mechanism of Disease (MoD)

Which DDR Inhibitors Are Being Investigated?

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ATR inhibitors

ATR inhibitors like tuvusertib (M1774) could potentially enhance the efficacy of DNA-damaging agents in cancer cells. Additionally, ATR inhibitors are being investigated as monotherapies and combination therapies against tumors with high levels of DNA damage.1,4,9,10

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ATR inhibitors

ATR inhibitors like tuvusertib (M1774) could potentially enhance the efficacy of DNA-damaging agents in cancer cells. Additionally, ATR inhibitors are being investigated as monotherapies and combination therapies against tumors with high levels of DNA damage.1,4,9,10

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ATM inhibitors

ATM inhibitors such as M4076 can increase the cell’s dependency on other DDR pathways, may sensitize cells to anticancer therapies, and may induce an innate immune response.6,11-13

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References
1. Blackford N, Jackson P. Mol Cell. 2017;66(6):801-817; 2. Ford JM, Kastan MB. In: Abeloff's Clinical Oncology. Elsevier. 2019:154-164; 3. Minten EV, Yu DS. Clin Oncol (R Coll Radiol). 2019;31(5):303-310; 4. Carrassa L, Damia G. Cancer Treat Rev. 2017;60:139-151; 5. Li Y, et al. Cell Rep. 2019;28(3):735-745; 6. Cremona CA, Behrens A. Oncogene. 2014;33(26):3351-3360; 7. Zenke FT, et al. Mol Cancer Ther. 2020;19(5):1091-1101; 8. Pospisilova M, et al. J Physiol Pharmacol. 2017;68(3):337-344; 9. ClinicalTrials.gov. Accessed June 28, 2023. https://clinicaltrials.gov/ct2/show/NCT04170153; 10. ClinicalTrials.gov. Accessed June 28, 2023. https://clinicaltrials.gov/ct2/show/NCT05396833; 11. Zimmermann A, et al. Mol Cancer Ther. 2022;21(6):859-870; 12. Zhang Q, et al. Cancer Res. 2019;79(15):3940-3951; 13. ClinicalTrials.gov. Accessed June 28, 2023. https://clinicaltrials.gov/ct2/show/NCT04882917.

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