Clinical and Molecular Characterization of a Rare EGFR cis Compound L833V/H835L Mutation in Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) with EGFR L833V/H835L in cis mutation remains poorly understood. We retrospectively reviewed the clinicopathologic features of NSCLC with either EGFR L833V or H835L mutation. The study population includes patients with NSCLC (n = 3,835) at Samsung Medical Center, Seoul, Korea. A total of eight patients with EGFR L833V/H835L in cis mutation were identified. Poorly differentiated histology (either micropapillary or solid patterns) presented in four of five resected cases. Four patients received EGFR tyrosine kinase inhibitors (TKIs) and achieved a median progression-free survival of 13 months. The oncogenic and therapeutic properties of the mutation were investigated through a combination of functional and biochemical analyses, utilizing both in vitro and in vivo models, and structural modeling. The L833V/H835L mutant exhibited oncogenic potential, transforming NIH-3T3 cells and promoting IL3-independent growth in Ba/F3 cells. Furthermore, EGFR TKIs effectively suppressed the mutant's oncogenic activity in both in vitro and in vivo studies. These phenomena are further supported by its increased kinase activity in structural modeling. Although rare, EGFR L833V/H835L in cis mutation represents a biologically oncogenic and clinically actionable variant in NSCLC. SIGNIFICANCE: Our study reveals the rare EGFR L833V/H835L cis mutation as an aggressive oncogenic driver in lung adenocarcinoma, highly responsive to EGFR-directed therapy. These findings provide crucial therapeutic strategies for patients with this specific EGFR variant, addressing a current gap in precision medicine.