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. Borger, Sridhar Ramaswamy, Toshi Shioda, Anthony J. Iafrate, Gad Getz, Charles M. Rudin, Mari Mino-Kenudson and Jeffrey A. Engelman ()
Additional contact information
Matthew J. Niederst: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
Lecia V. Sequist: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
John T. Poirier: Memorial Sloan Kettering Cancer Center, Thoracic Oncology Service
Craig H. Mermel: Broad Institute of MIT and Harvard, Cancer Genome Comparative Analysis Group
Elizabeth L. Lockerman: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
Angel R. Garcia: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
Ryohei Katayama: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
Carlotta Costa: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
Kenneth N. Ross: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
Teresa Moran: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
Emily Howe: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
Linnea E. Fulton: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
Hillary E. Mulvey: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
Lindsay A. Bernardo: Massachusetts General Hospital Cancer Center
Farhiya Mohamoud: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
Norikatsu Miyoshi: Harvard Medical School
Paul A. VanderLaan: Beth Israel Deaconess Medical Center, Harvard Medical School
Daniel B. Costa: Beth Israel Deaconess Medical Center, Harvard Medical School
Pasi A. Jänne: Belfer Institute of Applied Science, Dana Farber Cancer Institute
Darrell R. Borger: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
Sridhar Ramaswamy: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
Toshi Shioda: Harvard Medical School
Anthony J. Iafrate: Massachusetts General Hospital Cancer Center
Gad Getz: Harvard Medical School
Charles M. Rudin: Memorial Sloan Kettering Cancer Center, Thoracic Oncology Service
Mari Mino-Kenudson: Massachusetts General Hospital Cancer Center
Jeffrey A. Engelman: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms7377

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