{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:15:41Z","timestamp":1786976141209,"version":"build-2736575974"},"reference-count":54,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T00:00:00Z","timestamp":1606262400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:p>\n                    Small\u2010cell lung cancer (SCLC) occurs infrequently in never\/former light smokers. We sought to study this rare clinical subset through next\u2010generation sequencing (NGS) and by characterizing a representative patient\u2010derived 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\u2010derived model from one such patient (DFCI168) harboring an\n                    <jats:italic>NRAS<\/jats:italic>\n                    <jats:sup>Q61K<\/jats:sup>\n                    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                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a01), mixed non\u2010small\u2010cell lung carcinoma and SCLC (\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a04), unspecified poorly differentiated carcinoma (\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a01), or small\u2010cell carcinoma from different origins (\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a02).\n                    <jats:italic>RB1<\/jats:italic>\n                    and\n                    <jats:italic>TP53<\/jats:italic>\n                    mutations were found in four and five cases, respectively. Predicted driver mutations were detected in\n                    <jats:italic>EGFR<\/jats:italic>\n                    (\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a02),\n                    <jats:italic>NRAS<\/jats:italic>\n                    (\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a01),\n                    <jats:italic>KRAS<\/jats:italic>\n                    (\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a01),\n                    <jats:italic>BRCA1<\/jats:italic>\n                    (\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a01), and\n                    <jats:italic>ATM<\/jats:italic>\n                    (\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a01), and one case harbored a\n                    <jats:italic>TMPRSS2\u2010ERG<\/jats:italic>\n                    fusion. DFCI168 (\n                    <jats:italic>NRAS<\/jats:italic>\n                    <jats:sup>Q61K<\/jats:sup>\n                    ) exhibited marked sensitivity to MEK inhibitors\n                    <jats:italic>in\u00a0vitro<\/jats:italic>\n                    and\n                    <jats:italic>in\u00a0vivo.<\/jats:italic>\n                    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\n                    <jats:italic>NRAS<\/jats:italic>\n                    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\u2010harboring 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.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.12673","type":"journal-article","created":{"date-parts":[[2020,3,19]],"date-time":"2020-03-19T12:30:58Z","timestamp":1584621058000},"page":"27-42","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Genomic and pathological heterogeneity in clinically diagnosed small cell lung cancer in never\/light smokers identifies therapeutically targetable alterations"],"prefix":"10.1002","volume":"15","author":[{"given":"Atsuko","family":"Ogino","sequence":"first","affiliation":[{"name":"Department of Medical Oncology Dana\u2010Farber Cancer Institute Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihyun","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Medical 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