Genetic alterations and protein expression in combined small cell lung cancers and small cell lung cancers arising from lung adenocarcinomas after therapy with tyrosine kinase inhibitors

There are 2 hypotheses regarding the mechanism underlying the adenocarcinoma (AD) to small cell lung cancer (SCLC) transition in patients receiving Tyrosine kinase inhibitor (TKI) therapy: 1) AD gives rise to SCLC owing to the pressure of the TKI therapy, and 2) the SCLC coexists with the AD de novo, but is not detected in biopsy specimens of the heterogeneous tumor. In this study, we try to address this issue by examination the genetic alteration and protein expression profile between SCLC arising from AD, and SCLC in combined small cell lung cancers (CSCLC). In the former, the SCLC had the same genetic profile as the AD, and we strongly suggest that the transition was a consequence of TKI therapy. In the latter, genetic alterations and protein expression tended to differ between the NSCLC and SCLC components of the CSCLC. The results showed that EGFR and KRAS mutation were found in 1 but not both component of CSCLC, and the NSCLC component usually expressed the EGFR and RB1 proteins, whereas the SCLC component did not. This finding indicates that the NSCLC and SCLC components arose separately and that CSCLC are unsuitable for TKI therapy despite the presence of sensitive EGFR mutations.