RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer

Matthew J. Niederst, Lecia V. Sequist, John T. Poirier, Craig H. Mermel, Elizabeth L. Lockerman, Angel R. Garcia, Ryohei Katayama, Carlotta Costa, Kenneth N. Ross, Teresa Moran, Emily Howe, Linnea E. Fulton, Hillary E. Mulvey, Lindsay A. Bernardo, Farhiya Mohamoud, Norikatsu Miyoshi, Paul A. VanderLaan, Daniel B. Costa, Pasi A. Jänne, Darrell R. BorgerSridhar Ramaswamy, Toshi Shioda, Anthony J. Iafrate, Gad Getz, Charles M. Rudin, Mari Mino-Kenudson, Jeffrey A. Engelman

Research output: Contribution to journalArticlepeer-review


Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.

Original languageEnglish (US)
Article number6377
JournalNature Communications
StatePublished - 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

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