vx-970 and Lung-Neoplasms

The deubiquitinase ovarian tumor domain-containing 1 (OTUD1) has been considered as a tumor suppressor in many tumors, but there is minimal research on the role of OTUD1 in lung adenocarcinoma (LUAD) pathogenesis.. Bioinformatics analyses and western blot were applied for investigating OTUD1 expression in lung cancer and the drug that upregulated OTUD1. Kaplan-Meier analysis with log-rank test was used for survival analyses. IP-MS and co-IP were performed for identifying potential protein interactions with OTUD1. In vitro and in vivo assays were used for exploring the function of OTUD1 during the progression of LUAD.. OTUD1 was dramatically downregulated in tumors and cell lines of human lung cancer. OTUD1 inhibited proliferation and migration of lung cancer cells in vitro. Moreover, OTUD1 inhibited growth of xenografts in nude mice and formation of primary lung tumors in urethane-induced lung cancer model. Mechanistically, we showed that OTUD1 deubiquitinated and stabilized FHL1. Furthermore, we listed and identified VE-822 as a candidate agonist for OTUD1. VE-822 inhibited proliferation of lung adenocarcinoma both in vitro and in vivo.. These results indicated that the deubiquitinase OTUD1, which was upregulated by VE-822, inhibited the progression of LUAD in vitro and in vivo by deubiquitinating and stabilizing FHL1.

Topics: Adenocarcinoma of Lung; Animals; Cell Line, Tumor; Cell Proliferation; Deubiquitinating Enzymes; Female; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins; Lung Neoplasms; Mice; Mice, Nude; Muscle Proteins; Ubiquitin-Specific Proteases

Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations.. In a phase I trial, we combined sacituzumab govitecan, antibody-drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels.. Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥grade 4 adverse events occurred. Tumor regressions were observed in 2 patients with neuroendocrine prostate cancer, and a patient with small cell lung cancer transformed from EGFR-mutant non-small cell lung cancer.. ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors. See related commentary by Berg and Choudhury, p. 3557.

Topics: Camptothecin; Carcinoma, Non-Small-Cell Lung; Humans; Immunoconjugates; Lung Neoplasms; Male

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

M6620, a selective ATP-competitive inhibitor of the ATM and RAD3-related (ATR) kinase, is currently under investigation with radiation in patients with non-small cell lung cancer (NSCLC) brain metastases. We evaluated the DNA damage response (DDR) pathway profile of NSCLC and assessed the radiosensitizing effects of M6620 in a preclinical NSCLC brain metastasis model. Mutation analysis and transcriptome profiling of DDR genes and pathways was performed on NSCLC patient samples. NSCLC cell lines were assessed with proliferation, clonogenic survival, apoptosis, cell cycle, and DNA damage signaling and repair assays. NSCLC brain metastasis patient-derived xenograft models were used to assess intracranial response and overall survival.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Female; Heterografts; Humans; Isoxazoles; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Pyrazines; Treatment Outcome

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