Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress.

Small cell neuroendocrine cancers (SCNCs) are recalcitrant cancers arising from diverse primary sites that lack effective treatments. Using chemical genetic screens, we identified inhibition of ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, and topoisomerase I (TOP1), nuclear enzyme that suppresses genomic instability, as synergistically cytotoxic in small cell lung cancer (SCLC). In a proof-of-concept study, we combined M6620 (berzosertib), first-in-class ATR inhibitor, and TOP1 inhibitor topotecan in patients with relapsed SCNCs. Objective response rate among patients with SCLC was 36% (9/25), achieving the primary efficacy endpoint. Durable tumor regressions were observed in patients with platinum-resistant SCNCs, typically fatal within weeks of recurrence. SCNCs with high neuroendocrine differentiation, characterized by enhanced replication stress, were more likely to respond. These findings highlight replication stress as a potentially transformative vulnerability of SCNCs, paving the way for rational patient selection in these cancers, now treated as a single disease.
Competing Interests: Declaration of interests H.D., A.Z., and F.T.Z. are employees of Merck KGaA, Darmstadt, Germany. B.E. is an employee of the EMD Serono Research & Development Institute Inc., Billerica, MA, USA; a business of Merck KGaA, Darmstadt, Germany. J.P. was an employee of the EMD Serono Research & Development Institute Inc., Billerica, MA, USA at the time of study. A.T., and Y.P. report research funding to the institution from the following entities: EMD Serono Research & Development Institute Inc., Billerica, MA, USA, AstraZeneca, Tarveda Therapeutics, and Prolynx Inc.
(Published by Elsevier Inc.)