Lung cancer (Amsterdam, Netherlands) · 2026
BRAF fusions define therapeutic vulnerability and tyrosine kinase inhibitor resistance in non-small cell lung cancer.
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Wang Kai, Yi Chao, Ning Xiong, Xiong Dalin, Wang Song, Wu Xiaoying, Bao Hua, Jiang Yuan, Deng Hongyu, Tang Faqing
Аннотация
BACKGROUND: BRAF fusions are rare but clinically relevant oncogenic events in non-small cell lung cancer (NSCLC), yet their molecular characteristics and optimal management remain unclear.
METHODS: We retrospectively analyzed 97 patients with NSCLC harboring kinase domain-retaining BRAF fusions, stratified into de novo (N = 43) and acquired (N = 54) groups. Clinical and genomic features were compared across subgroups and comparator driver cohorts.
RESULTS: We identified 104 BRAF fusions involving 53 unique partner genes, 29 of which were novel. Common partners included AGK (12.5%), IGR (11.5%), ZC3HAV1 (7.7%), TRIM24 (5.8%), and MKRN1 (5.8%). IGR and DTNB were more commonly observed in de novo cases, whereas AGK-BRAF fusions predominated in acquired cases. Among de novo cases, 65.1% lacked co-occurring drivers. ZNF703 mutations and NRF2 pathway alterations were recurrently enriched in BRAF fusion-only tumors, while CTNNB1 and NKX2-1 mutations were enriched versus ALK-rearranged cases. BRAF fusions co-occurring with other drivers showed enrichment of KMT2C and RTK-RAS pathway mutations, with TP53 mutations enriched compared to RET-rearranged tumors. One patient with TRIM24-BRAF and EGFR exon 19 deletion derived clinical benefit from dual MEK and EGFR inhibition. Acquired BRAF fusions were frequently detected after EGFR-TKI therapy, representing the predominant alteration in 63.0% of cases. Median progression-free survival on prior EGFR-TKIs aligned with clinical trial benchmarks.
CONCLUSIONS: BRAF fusions in NSCLC are molecularly heterogeneous, with distinct genomic landscapes between de novo and acquired cases. These findings support repeated comprehensive genomic profiling at progression and suggest that pathway-directed combinations, such as MEK plus EGFR inhibition, may offer individualized treatment options for selected patients.
METHODS: We retrospectively analyzed 97 patients with NSCLC harboring kinase domain-retaining BRAF fusions, stratified into de novo (N = 43) and acquired (N = 54) groups. Clinical and genomic features were compared across subgroups and comparator driver cohorts.
RESULTS: We identified 104 BRAF fusions involving 53 unique partner genes, 29 of which were novel. Common partners included AGK (12.5%), IGR (11.5%), ZC3HAV1 (7.7%), TRIM24 (5.8%), and MKRN1 (5.8%). IGR and DTNB were more commonly observed in de novo cases, whereas AGK-BRAF fusions predominated in acquired cases. Among de novo cases, 65.1% lacked co-occurring drivers. ZNF703 mutations and NRF2 pathway alterations were recurrently enriched in BRAF fusion-only tumors, while CTNNB1 and NKX2-1 mutations were enriched versus ALK-rearranged cases. BRAF fusions co-occurring with other drivers showed enrichment of KMT2C and RTK-RAS pathway mutations, with TP53 mutations enriched compared to RET-rearranged tumors. One patient with TRIM24-BRAF and EGFR exon 19 deletion derived clinical benefit from dual MEK and EGFR inhibition. Acquired BRAF fusions were frequently detected after EGFR-TKI therapy, representing the predominant alteration in 63.0% of cases. Median progression-free survival on prior EGFR-TKIs aligned with clinical trial benchmarks.
CONCLUSIONS: BRAF fusions in NSCLC are molecularly heterogeneous, with distinct genomic landscapes between de novo and acquired cases. These findings support repeated comprehensive genomic profiling at progression and suggest that pathway-directed combinations, such as MEK plus EGFR inhibition, may offer individualized treatment options for selected patients.