Novel ETV1 mutation in small cell lung cancer transformation resistant to EGFR tyrosine kinase inhibitors

BACKGROUND: Non-small cell lung cancer (NSCLC) patients harboring mutations in the epidermal growth factor receptor (EGFR) gene respond dramatically to EGFR tyrosine kinase inhibitors (TKIs). However, these patients inevitably develop acquired resistance to EGFR-TKIs. Among them, small cell lung cancer (SCLC) transformation is a relatively rare mechanism. METHODS: We used a 639 cancer-relevant gene panel to detect genetic differences in tissues before and after EGFR-TKIs resistance caused by SCLC transformation. In vitro experiments were conducted to study the role of ETS variant transcription factor 1 (ETV1) on SCLC transformation and EGFR-TKIs resistance. RESULTS: We present two EGFR-mutant lung adenocarcinoma (LUAD) patients. One patient, with EGFR exon 19 deletion (Ex19del), accepted first-line gefitinib treatment and then received osimertinib treatment due to acquisition of an EGFR-T790M mutation. A novel ETV1 mutation (p.P159S) was detected in the SCLC tissue after osimertinib resistance when not coexisting with T790M. The other patient harbored an EGFR exon 21 mutation (p.L858R), and had a long-lasting response to first-line gefitinib, and then transformed to SCLC after TKI resistance. A previously unreported ETV1 mutation (p.E462Q) was detected in the SCLC tissue. In vitro, ETV1 p.E462Q and p.P159S mutations participated in neuroendocrine differentiation by inducing the expression of achaete-scute homolog 1 (ASCL1) and promoting the proliferation of H69 cells. ETV1 p.E462Q and p.P159S mutations were also resistant to gefitinib and osimertinib after introduction into H358 cells. CONCLUSIONS: Novel ETV1 p.E462Q and p.P159S mutations were found in the SCLC tissues of TKIs-resistant LUAD patients, providing a new understanding of ETV1 involvement in acquired resistance to EGFR-TKIs via SCLC transformation.