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

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.

SUBMITTER: Thomas A

PROVIDER: S-EPMC8048383 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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

Thomas Anish A Takahashi Nobuyuki N Rajapakse Vinodh N VN Zhang Xiaohu X Sun Yilun Y Ceribelli Michele M Wilson Kelli M KM Zhang Yang Y Beck Erin E Sciuto Linda L Nichols Samantha S Elenbaas Brian B Puc Janusz J Dahmen Heike H Zimmermann Astrid A Varonin Jillian J Schultz Christopher W CW Kim Sehyun S Shimellis Hirity H Desai Parth P Klumpp-Thomas Carleen C Chen Lu L Travers Jameson J McKnight Crystal C Michael Sam S Itkin Zina Z Lee Sunmin S Yuno Akira A Lee Min-Jung MJ Redon Christophe E CE Kindrick Jessica D JD Peer Cody J CJ Wei Jun S JS Aladjem Mirit I MI Figg William Douglas WD Steinberg Seth M SM Trepel Jane B JB Zenke Frank T FT Pommier Yves Y Khan Javed J Thomas Craig J CJ

Cancer cell 20210401 4

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 ...[more]

PMID: 33848478

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Project description:BackgroundThe identification of novel targets is of paramount importance to develop more effective drugs and improve the treatment of non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths worldwide. Since cells alter their metabolic rewiring during tumorigenesis and along cancer progression, targeting key metabolic players and metabolism-associated proteins represents a valuable approach with a high therapeutic potential. Metabolic fitness relies on the functionality of heat shock proteins (HSPs), molecular chaperones that facilitate the correct folding of metabolism enzymes and their assembly in macromolecular structures.MethodsGene fitness was determined by bioinformatics analysis from available datasets from genetic screenings. HSPD1 expression was evaluated by immunohistochemistry from formalin-fixed paraffin-embedded tissues from NSCLC patients. Real-time proliferation assays with and without cytotoxicity reagents, colony formation assays and cell cycle analyses were used to monitor growth and drug sensitivity of different NSCLC cells in vitro. In vivo growth was monitored with subcutaneous injections in immune-deficient mice. Cell metabolic activity was analyzed through extracellular metabolic flux analysis. Specific knockouts were introduced by CRISPR/Cas9.ResultsWe show heat shock protein family D member 1 (HSPD1 or HSP60) as a survival gene ubiquitously expressed in NSCLC and associated with poor patients' prognosis. HSPD1 knockdown or its chemical disruption by the small molecule KHS101 induces a drastic breakdown of oxidative phosphorylation, and suppresses cell proliferation both in vitro and in vivo. By combining drug profiling with transcriptomics and through a whole-genome CRISPR/Cas9 screen, we demonstrate that HSPD1-targeted anti-cancer effects are dependent on oxidative phosphorylation and validated molecular determinants of KHS101 sensitivity, in particular, the creatine-transporter SLC6A8 and the subunit of the cytochrome c oxidase complex COX5B.ConclusionsThese results highlight mitochondrial metabolism as an attractive target and HSPD1 as a potential theranostic marker for developing therapies to combat NSCLC.

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

Publications

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

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