Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Platinum-based chemotherapy is standard for lung cancer, but poor outcomes persist.
• The DNA-damage response (DDR) pathway, regulated by ATR kinase, contributes to treatment resistance.
• Inhibiting ATR kinase may sensitize cancer cells to DNA-damaging agents, but in vivo data are limited.

Purpose of the Study:

• To evaluate the efficacy of VX-970, a clinical ATR inhibitor, in lung cancer.
• To compare VX-970 with a Chk1 inhibitor in preclinical lung cancer models.
• To assess the in vivo combination of VX-970 and cisplatin in patient-derived xenografts.

Main Methods:

• Profiling VX-970 in vitro across lung cancer cell lines and primary tumors.
• Comparing VX-970 with a Chk1 inhibitor in vitro.
• Assessing VX-970's effect on ATR activity and cisplatin efficacy in vivo using patient-derived lung xenografts.

Main Results:

• VX-970 sensitized a significant proportion of lung cancer models to DNA-damaging drugs in vitro, distinct from Chk1 inhibition.
• In vivo, VX-970 blocked tumor ATR activity and potentiated cisplatin efficacy.
• The combination of VX-970 and cisplatin achieved complete tumor growth inhibition in cisplatin-insensitive models and durable regression in a sensitive model.

Conclusions:

• VX-970 demonstrates significant preclinical efficacy in enhancing platinum-based chemotherapy in lung cancer.
• ATR inhibition offers a promising strategy to overcome chemotherapy resistance in lung cancer.
• These findings support the clinical investigation of VX-970 for lung cancer treatment.