Journal Article

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

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

2015

Overview

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. Resistance to tyrosine kinase inhibitors occurs in treatments of non-small-cell lung cancers (NSCLCs) with EGFR mutations but the mechanisms underlying this acquired resistance are unknown. Here the authors examine the molecular changes that occur in resistant cancers that transition from NSCLC to small-cell lung cancer phenotype and implicate loss of retinoblastoma in this process.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
• Subject: 13/106 / 13/2 / 13/95 / 38/39 / 38/77 / 692/420/755 / 692/699/67/1612 / 82 / 82/51 / Adenocarcinoma - drug therapy / Adenocarcinoma - genetics / Adenocarcinoma - metabolism / Adenocarcinoma - pathology / Adenocarcinoma of Lung / Afatinib / Aniline Compounds - pharmacology / Antineoplastic Agents - pharmacology / bcl-X Protein - genetics / bcl-X Protein - metabolism / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - metabolism / Carcinoma, Non-Small-Cell Lung - pathology / Cell Line, Tumor / Disease Progression / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / ErbB Receptors - antagonists & inhibitors / ErbB Receptors - deficiency / ErbB Receptors - genetics / Erlotinib Hydrochloride - pharmacology / Gefitinib / Gene Expression Regulation, Neoplastic / Humanities and Social Sciences / Humans / Lung - drug effects / Lung - metabolism / Lung - pathology / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / multidisciplinary / Mutation / Protein Kinase Inhibitors - pharmacology / Proto-Oncogene Proteins c-bcl-2 - genetics / Proto-Oncogene Proteins c-bcl-2 - metabolism / Quinazolines - pharmacology / Recurrence / Retinoblastoma Protein - deficiency / Retinoblastoma Protein - genetics / Science / Science (multidisciplinary) / Signal Transduction / Small Cell Lung Carcinoma - drug therapy / Small Cell Lung Carcinoma - genetics / Small Cell Lung Carcinoma - metabolism / Small Cell Lung Carcinoma - pathology / Sulfonamides - pharmacology