vx-970 and Small-Cell-Lung-Carcinoma

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.

Topics: Aged; Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; DNA Replication; DNA Topoisomerases, Type I; Genomic Instability; Humans; Isoxazoles; Lung Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrazines; Signal Transduction; Small Cell Lung Carcinoma

Although several ATR inhibitors are in development, there are unresolved questions regarding their differential potency, molecular signatures of patients with cancer for predicting activity, and most effective therapeutic combinations. Here, we elucidate how to improve ATR-based chemotherapy with the newly developed ATR inhibitor, M4344 using

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Cell Proliferation; Deoxycytidine; DNA Replication; Female; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Isoxazoles; Lung Neoplasms; Mice; Mice, Nude; Morpholines; Pyrazines; Pyrazoles; Small Cell Lung Carcinoma; Topotecan; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Small cell lung cancer (SCLC) is generally regarded as very difficult to treat, mostly due to the development of metastases early in the disease and a quick relapse with resistant disease. SCLC patients initially show a good response to treatment with the DNA damaging agents cisplatin and etoposide. This is, however, quickly followed by the development of resistant disease, which urges the development of novel therapies for this type of cancer. In this study, we set out to compile a comprehensive overview of the vulnerabilities of SCLC. A functional genome-wide screen where all individual genes were knocked out was performed to identify novel vulnerabilities of SCLC. By analysis of the knockouts that were lethal to these cancer cells, we identified several processes to be synthetic vulnerabilities in SCLC. We were able to validate the vulnerability to inhibition of the replication stress response machinery by use of Chk1 and ATR inhibitors. Strikingly, SCLC cells were more sensitive to these inhibitors than nontransformed cells. In addition, these inhibitors work synergistically with either etoposide and cisplatin, where the interaction is largest with the latter. ATR inhibition by VE-822 treatment in combination with cisplatin also outperforms the combination of cisplatin with etoposide

Topics: A549 Cells; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Ataxia Telangiectasia Mutated Proteins; Cell Survival; Checkpoint Kinase 1; Cisplatin; CRISPR-Associated Protein 9; DNA Damage; Drug Synergism; Etoposide; Humans; Isoxazoles; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Protein Kinase Inhibitors; Pyrazines; Small Cell Lung Carcinoma; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Benzodiazepinones; cdc25 Phosphatases; Cell Cycle; Cell Line, Tumor; Checkpoint Kinase 1; DNA Damage; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Isoxazoles; Lung Neoplasms; Male; Mice; Mice, Nude; Molecular Targeted Therapy; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyrazines; Pyrazoles; RNA, Messenger; Signal Transduction; Small Cell Lung Carcinoma; Xenograft Model Antitumor Assays