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


ABSTRACT: 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 NRASQ61K 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 nonpulmonary origin or of mixed histology and included atypical carcinoid (n = 1), mixed non-small-cell lung carcinoma 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 four and five cases, respectively. Predicted driver mutations were detected in EGFR (n = 2), NRAS (n = 1), KRAS (n = 1), BRCA1 (n = 1), and ATM (n = 1), and one case harbored a TMPRSS2-ERG fusion. DFCI168 (NRASQ61K ) 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.

SUBMITTER: Ogino A 

PROVIDER: S-EPMC7782083 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Ogino Atsuko A   Choi Jihyun J   Lin Mika M   Wilkens Margaret K MK   Calles Antonio A   Xu Man M   Adeni Anika E AE   Chambers Emily S ES   Capelletti Marzia M   Butaney Mohit M   Gray Nathanael S NS   Gokhale Prafulla C PC   Palakurthi Sangeetha S   Kirschmeier Paul P   Oxnard Geoffrey R GR   Sholl Lynette M LM   Jänne Pasi A PA  

Molecular oncology 20201125 1


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<sup>Q61K</sup> mutation and characterize  ...[more]

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