Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress.
Cancer Cell
; 39(4): 566-579.e7, 2021 04 12.
Article
en En
| MEDLINE
| ID: mdl-33848478
ABSTRACT
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.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Pirazinas
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Carcinoma Pulmonar de Células Pequeñas
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Proteínas de la Ataxia Telangiectasia Mutada
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Isoxazoles
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Neoplasias Pulmonares
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Recurrencia Local de Neoplasia
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Cancer Cell
Asunto de la revista:
NEOPLASIAS
Año:
2021
Tipo del documento:
Article