DNA DAMAGE RESPONSE

The ATR pathway

ATR is thought to be activated in response to DNA damage, such as double-strand breaks and replication stress. In cancer, a loss of ATM-p53 signaling is common and leads to dependence of tumor cells on ATR to survive DNA damage.1-3

Replication stress results in sections of exposed single-stranded DNA. Replication Protein A (RPA) binds to and protects single-stranded DNA. Accumulation of RPA results in activation of the ATR pathway, which regulates cell cycle progression and promotes fork repair.4,5

Berzosertib (ATR inhibitor)

Description and Mechanism of Action:

Berzosertib is an investigational intravenous inhibitor of ATR, which facilitates DNA repair. ATR inhibition is thought to exacerbate oncogenic stress and promote cell death.5,6

Berzosertib is designed to block ATR activity in cells leading to increased double-strand DNA breaks that cannot be repaired and driving tumor cell death.6

The ATR Pathway Berzosertib

Areas of Interest:

TRIALS

DDRiver SCLC 2507 (NCT04768296)

A phase II, open-label, single-arm study evaluating berzosertib (M6620) with topotecan for the treatment of patients with relapsed, platinum-resistant small cell lung cancer (SCLC).

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M1774 (ATR inhibitor)

Description and Mechanism of Action:

M1774 is a potent, orally administered, selective ATR inhibitor. ATR inhibition is thought to exacerbate oncogenic stress and promote cell death.5,8

M1774 is designed to block ATR activity in cells leading to increased double-strand DNA breaks that cannot be repaired and driving tumor cell death.5,6,8,9

The ATR Pathway M1774

Areas of Interest:

TRIALS

DDRiver Solid Tumors 30110 (NCT04170153)

A phase I, open-label trial evaluating M1774 in patients with locally advanced or metastatic unresectable solid tumors.

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DDRiver clinical trial program

DDRiver

Are you interested in learning more about a clinical trial program investigating the potential anticancer effect of inhibiting the DNA damage response (DDR) pathway?

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Pathways Under Investigation

DNA-PK

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Abbreviations:
ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia RAD3-related; DNA-PK, DNA-dependent protein kinase.

References:

  1. Cimprich KA, Cortez D. ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol. 2008;9(8):616-627.
  2. Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev. 2012;26:1268-1286.
  3. Hall AB, Newsome D, Wang Y, et al. Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970. Oncotarget. 2014;5(14):5674-5685.
  4. Zeman MK, Cimprich KA. Causes and consequences of replication stress. Nat Cell Biol. 2014;16(1):2-9.
  5. Blackford AN, Jackson SP. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol Cell. 2017;66:801-817.
  6. Das S, Berlin J, Schulten J, Diaz-Padilla I, Whiseant JG. Berzosertib. Drugs Fut. 2019;44(7):517-525.
  7. Berzosertib + topotecan in relapsed platinum-resistant small-cell lung cancer (DDRiver SCLC 250). ClinicalTrials.gov identifier: NCT04768296. Updated October 28, 2021. Accessed November 4, 2021. https://clinicaltrials.gov/ct2/show/NCT04768296
  8. Yap TA, Tolcher AW, Plummer ER, et al. A first-in-human phase I study of ATR inhibitor M1774 in patients with solid tumors. J Clin Oncol. 2021;39(suppl 15):TPS3153. doi:10.1200/JCO.2021.39.15_suppl.TPS315
  9. Carrassa L, Damia G. DNA damage response inhibitors: mechanisms and potential applications in cancer therapy. Cancer Treat Rev. 2017;60:139-151.
  10. M1774 in participants with metastatic or locally advanced unresectable solid tumors (DDRiver Solid Tumors 301). ClinicalTrials.gov identifier: NCT04170153. Updated September 30, 2021. Accessed November 4, 2021. https://www.clinicaltrials.gov/ct2/show/NCT04170153

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