Acquired BRAF N581S mutation mediated resistance to gefitinib and responded to dabrafenib plus trametinib

Abstract

Objectives: BRAFG469A and V600E were reported as the mechanisms of acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer patients. Here, we described a rare case of BRAF N581S after gefitinib resistance and response to BRAF inhibitor plus MEK inhibitor.

Materials and methods: Next-generation sequencing (NGS) was performed on the tumor tissue and plasma samples of a patient with metastatic lung adenocarcinoma harboring EGFR exon 19 deletion (EGFR 19del).

Results: EGFR 19del and MET amplification was detected after resistance to the initial gefitinib therapy. After 9 months of treatment with gefitinib plus crizotinib, the disease progressed again. NGS revealed the known EGFR 19del and a BRAF N581S missense mutation after progression. The patient obtained durable clinical benefit upon treatment with dabrafenib plus trametinib, achieving a progression-free survival (PFS) of more than 33 months.

Conclusion: BRAF N581S mutation could be explored as one kind of mechanism of acquired resistance to EGFR-TKIs. Combined inhibition of BRAF and MEK is a potential therapeutic strategy.

Keywords: BRAF N581S; Dabrafenib; Gefitinib; Trametinib.