Journal of Cancer Research and Clinical Oncology, Journal Year: 2024, Volume and Issue: 150(11)

Published: Nov. 14, 2024

Abstract Purpose Small cell lung cancer (SCLC) has an extremely poor prognosis. Despite high initial response rates to chemotherapy and modest survival improvements with the addition of immune checkpoint inhibitors (ICI), almost all patients experience relapse fatal outcomes. Recent genomic insights uncovered extensive molecular heterogeneity in uniform loss RB1 TRP53 . Additionally, defective DNA mismatch repair (MMR) recently been described some SCLC cases. Here, we generated a novel mouse model capturing MMR deficiency assessed immunotherapy responses. Methods We developed MMR-deficient genetically engineered (GEMM) by introducing conditional Msh2 gene, crucial for maintaining integrity, into standard Rb1 fl/fl ; Trp53 (RP) model. Genomic characteristics preclinical therapy responses were evaluated focusing on overall whole exome sequencing (WES) analyses. Results MMR-defective tumors ( (RPM)) later than MMR-proficient mice. However, time from tumor manifestation death affected animals was substantially shortened (median 55 days RP vs. 46.5 RPM), indicating increased aggressiveness tumors. RPM exhibited deficiency, mutational burden (TMB), elevated load candidate neoantigens, compared lesions p = 0.0106), suggesting immunogenicity. Importantly, significantly improved when exposed ICI. Conclusion propose as suitable system mimic TMB. provide vivo evidence that enhances ICI sensitivity. These findings could contribute stratifying immunotherapy, thereby improving treatment

Language: Английский