Genomic and pathological heterogeneity in clinically diagnosed small cell lung cancer in never/light smokers identifies therapeutically targetable alterations.

Small cell lung cancer (SCLC) occurs infrequently in never/former light smokers. We sought to study this rare clinical subset through next generation sequencing (NGS) and by characterizing a representative patient derived model. We performed targeted NGS, as well as comprehensive pathological evaluation, in 11 never/former light smokers with clinically diagnosed SCLC. We established a patient derived model from one such patient (DFCI168) harboring an NRAS(Q61K) mutation and characterized the sensitivity of this model to MEK and TORC1/2 inhibitors. Despite the clinical diagnosis of SCLC, the majority (8/11) of cases were either of non-pulmonary origin or of mixed histology and included atypical carcinoid (n=1), mixed non-small cell lung carcinoma (NSCLC) and SCLC (n=4), unspecified poorly differentiated carcinoma, (n=1) or small cell carcinoma from different origins (n=2). RB1 and TP53 mutations were found in 4 and 5 cases, respectively. Predicted driver mutations were detected in EGFR (n=2), NRAS (n=1), KRAS (n=1), BRCA1 (n=1), ATM (n=1) and one case harbored a TMPRSS2-ERG fusion. DFCI168 (NRAS(Q61K) ) exhibited marked sensitivity to MEK inhibitors in vitro and in vivo. The combination of MEK and mTORC1/2 inhibitors synergized to prevent compensatory mTOR activation, resulting in prolonged growth inhibition in this model and in three other NRAS-mutant lung cancer cell lines. SCLC in never/former light smokers is rare and is potentially a distinct disease entity comprised of oncogenic driver mutation-harboring carcinomas morphologically and/or clinically mimicking SCLC. Comprehensive pathologic review integrated with genomic profiling is critical in refining the diagnosis and in identifying potential therapeutic options.