Therapeutic vulnerabilities and pan-cancer landscape of BRAF class III mutations in epithelial solid tumors

作者：Eylül Özgü, Benjamin G. Kaplan, Smruthy Sivakumar, Ethan S. Sokol, Esranur Aydın, Ünal Metin Tokat, Ashkan Adibi, Ebru Gül Karakoç, Jiancheng Hu, Razelle Kurzrock, Mutlu Demiray · 发表于：BJC Reports · 年份：2024 · DOI：10.1038/s44276-024-00086-2 · 被引用次数：6 · 研究领域：Melanoma and MAPK Pathways、Lung Cancer Treatments and Mutations、Colorectal Cancer Treatments and Studies

BACKGROUND: Kinase-impaired class III BRAF mutations have recently received attention as a possible prognostic factor and therapeutic target. Class III BRAF variants differ from class I and class II mutations in terms of mechanism of pathway activation and therapeutic vulnerabilities. Genomic landscape analyses of tumors in large real-world cohorts represent a great opportunity to further characterize tumor-related molecular events and treatment vulnerabilities, however, such data is not yet available for tumors with BRAF class III mutations. METHODS: We investigated the pan-cancer genomic landscape of BRAF class III mutations in 376,302 patients. Patients had comprehensive genomic profiling either by FoundationOne® or FoundationOne®CDx from formalin-fixed, paraffin embedded tissue biopsies. 2 patient cases that harbored BRAF class III mutations who demonstrated dramatic response to anti-EGFR treatment were presented. RESULTS: BRAF class III mutations are likely to co-occur with RAF1, NRAS and HRAS alterations, while concomitant KRAS alterations were rare. Moreover, we found that alterations that predict resistance to anti-EGFR agents were significantly less common in tumors harboring BRAF class III mutations, which is of great importance as anti-EGFR therapies are a potential targeted treatment option in these tumors. DISCUSSION: Our findings suggest a heterogenous interplay of oncogenic alterations in BRAF class III mutated tumors and have important implications for the mol...