Cancer Vulnerabilities Through Targeting the ATR/Chk1 and ATM/Chk2 Axes in the Context of DNA Damage

Abstract

Eliciting DNA damage in tumor cells continues to be one of the most successful strategies against cancer. This is the case for classical chemotherapy drugs and radiotherapy. In the modern era of personalized medicine, this strategy tries to identify specific vulnerabilities found in each patient's tumor, to inflict DNA damage in certain cell contexts that end up in massive cancer cell death. Cells rely on multiple DNA repair pathways to fix DNA damage, but cancer cells frequently exhibit defects in these pathways, many times being tolerant to the damage. Key vulnerabilities, such as BRCA1/BRCA2 mutations, have been exploited with PARP inhibitors, leveraging synthetic lethality to selectively kill tumor cells and improving patients' survival. In the DNA damage response (DDR) network, kinases ATM, ATR, Chk1, and Chk2 coordinate DNA repair, cell cycle arrest, and apoptosis. Inhibiting these proteins enhances tumor sensitivity to DNA-damaging therapies, especially in DDR-deficient cancers. Several small-molecule inhibitors targeting ATM/Chk2 or ATR/Chk1 are currently being tested in preclinical and/or clinical settings, showing promise in cancer models and patients. Additionally, pharmacological blockade of ATM/Chk2 and ATR/Chk1 axes enhances the effects of immunotherapy by increasing tumor immunogenicity, promoting T-cell infiltration and activating immune responses. Combining ATM/Chk2- or ATR/Chk1-targeting drugs with conventional chemotherapy, radiotherapy or immune checkpoint inhibitors offers a compelling strategy to improve treatment efficacy, overcome resistance, and enhance patients' survival in modern oncology.

Keywords: ATM; ATR; Chk1; Chk2; DNA damage; immunotherapy; synthetic lethality.

Figure 1

Scheme showing the different causes and types of DNA damage induced by single-strand breaks (SSBs), together with their corresponding DNA damage response mechanisms. Agents causing SSBs include base mismatch, base damage or bulky lesions, which are repaired by mismatch mediated repair (MMR), base excision repair (BER) or nucleotide excision repair (NER), respectively.

Figure 2

Scheme showing causes and types of DNA damage induced by double-strand breaks (DSBs), together with their corresponding DNA damage response mechanisms. DBBs can be caused by ionizing radiation or certain drugs. The repair process can be performed by the non-homologous end joining (NHEJ) process or by homologous recombination (HR). Only a handful of relevant proteins are represented in the scheme, albeit many more ones participate in these repair mechanisms, especially in HR.

Figure 3

Crosstalk between Chk1/ATR and Chk2/ATM. Replication stress and ionizing radiation can induce activation of Chk1/ATR and Chk2/ATM pathways, respectively, converging in cell cycle arrest. In addition, the Chk1/ATR/Wee1 axis can recruit Rad51/BRCA1, triggering homologous recombination (HR).

Figure 4

Examples of synthetic lethality due to drug inhibition or gene loss/gene silencing of ATR, Chk2, ATM, and Chk1 kinases in conjunction with other drugs or defective genes implicated in DDR, cell cycle or chromatin remodeling.