Open AccessCoordinate Direct Input of Both KRAS and IGF1 Receptor to Activation of PI3 kinase in KRAS -Mutant Lung Cancer
Author(s) -
Míriam MolinaArcas,
David C. Hancock,
Clare Sheridan,
Madhu Kumar,
Julian Downward
Publication year - 2013
Publication title -
cancer discovery
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.795
H-Index - 163
eISSN - 2159-8290
pISSN - 2159-8274
DOI - 10.1158/2159-8290.cd-12-0446
Subject(s) - kras , pi3k/akt/mtor pathway , cancer research , insulin like growth factor 1 receptor , receptor tyrosine kinase , mek inhibitor , mapk/erk pathway , tyrosine kinase , cancer , protein kinase b , biology , lung cancer , kinase , targeted therapy , signal transduction , medicine , receptor , microbiology and biotechnology , colorectal cancer , biochemistry , genetics , growth factor
Using a panel of non-small cell lung cancer (NSCLC) lines, we show here that MAP-ERK kinase (MEK) and RAF inhibitors are selectively toxic for the KRAS-mutant genotype, whereas phosphoinositide 3-kinase (PI3K), AKT, and mTOR inhibitors are not. IGF1 receptor (IGF1R) tyrosine kinase inhibitors also show selectivity for KRAS-mutant lung cancer lines. Combinations of IGF1R and MEK inhibitors resulted in strengthened inhibition of KRAS-mutant lines and also showed improved effectiveness in autochthonous mouse models of Kras-induced NSCLC. PI3K pathway activity is dependent on basal IGF1R activity in KRAS-mutant, but not wild-type, lung cancer cell lines. KRAS is needed for both MEK and PI3K pathway activity in KRAS-mutant, but not wild-type, lung cancer cells, whereas acute activation of KRAS causes stimulation of PI3K dependent upon IGF1R kinase activity. Coordinate direct input of both KRAS and IGF1R is thus required to activate PI3K in KRAS-mutant lung cancer cells.
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