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

Nature Communications
Matthew J NiederstJeffrey A Engelman

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.

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Datasets Mentioned

BETA
GSE64765
GSE64766

Methods Mentioned

BETA
biopsy
biopsies
xenograft
PCR
transfection

Software Mentioned

Applied
R
muTect
Agilent CytoGenomics
Bioconductor
R Bioconductor
Biosystems LifeScope

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