Details

Autor(en) / Beteiligte

• Sharifnia, Tanaz
• Rusu, Victor
• Piccioni, Federica
• Bagul, Mukta
• Imielinski, Marcin
• Cherniack, Andrew D.
• Pedamallu, Chandra Sekhar
• Wong, Bang
• Wilson, Frederick H.
• Garraway, Levi A.
• Altshuler, David
• Golub, Todd R.
• Root, David E.
• Subramanian, Aravind
• Meyerson, Matthew

Titel

Genetic modifiers of EGFR dependence in non-small cell lung cancer

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2014-12, Vol.111 (52), p.18661-18666

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• Significance Non-small cell lung cancers (NSCLCs) harboring mutations in the epidermal growth factor receptor ( EGFR ) gene are often singularly reliant on EGFR activity for tumor cell survival, but the genetic basis for this dependence is not fully understood. In this study, we have performed a screen to identify a spectrum of kinase genes whose overexpression can overcome NSCLC cells’ reliance on EGFR. Using both unbiased and targeted approaches, we demonstrate that these genes commonly bypass dependence on EGFR through reactivation of downstream signaling pathways. Lung adenocarcinomas harboring activating mutations in the epidermal growth factor receptor ( EGFR ) represent a common molecular subset of non-small cell lung cancer (NSCLC) cases. EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and thus represent a dependency in NSCLCs harboring these alterations, but the genetic basis of EGFR dependence is not fully understood. Here, we applied an unbiased, ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR -mutant NSCLC cells. This approach identified 18 kinase and kinase-related genes whose overexpression can substitute for EGFR in EGFR-dependent PC9 cells, and these genes include seven of nine Src family kinase genes, FGFR1 , FGFR2 , ITK , NTRK1 , NTRK2 , MOS , MST1R , and RAF1 . A subset of these genes can complement loss of EGFR activity across multiple EGFR-dependent models. Unbiased gene-expression profiling of cells overexpressing EGFR bypass genes, together with targeted validation studies, reveals EGFR-independent activation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT pathways. Combined inhibition of PI3K-mTOR and MEK restores EGFR dependence in cells expressing each of the 18 EGFR bypass genes. Together, these data uncover a broad spectrum of kinases capable of overcoming dependence on EGFR and underscore their convergence on the PI3K-AKT and MEK-ERK signaling axes in sustaining EGFR-independent survival.