A molecular glue RBM39-degrader induces synthetic lethality in cancer cells with homologous recombination repair deficiency.

ABSTRACT: E7820 and Indisulam (E7070) are sulfonamide molecular glues that modulate RNA splicing by degrading the splicing factor RBM39 via ternary complex formation with the E3 ligase adaptor DCAF15. To identify biomarkers of the antitumor efficacy of E7820, we treated patient-derived xenograft (PDX) mouse models established from 42 patients with solid tumors. The overall response rate was 38.1% (16 PDXs), and tumor regression was observed across various tumor types. Exome sequencing of the PDX genome revealed that loss-of-function mutations in genes of the homologous recombination repair (HRR) system, such as ATM, were significantly enriched in tumors that responded to E7820 (p = 4.5 × 10³). Interestingly, E7820-mediated double-strand breaks in DNA were increased in tumors with BRCA2 dy

SUBMITTER: Kohsaka S 

PROVIDER: S-EPMC11126574 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature