Rare EGFR cis compound L833V/H835L mutation in non-small cell lung cancer is oncogenic and a therapeutic target of EGFR tyrosine kinase inhibitors

Non-small cell lung cancer (NSCLC) with EGFR L833V/H835L in cis mutation remains poorly understood. We retrospectively reviewed the clinicopathologic features NSCLC with either EGFR L833V or H835L mutation. The study population includes NSCLC patients (n=3835) at Samsung Medical Center, Seoul, Korea. A total of 8 patients with EGFR L833V/H835L in cis mutation were identified. Poorly differentiated histology (either micropapillary or solid patterns) presented in 4 of 5 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.