Abstract
The EGF-receptor (EGFR) and downstream signaling molecules have emerged as promising targets for inhibition by small molecules in the treatment of nonsmall cell lung cancer (NSCLC). In this study expression of pivotal signaling molecules in the EGFR pathway were used to predict response to inhibitors of the EGFR signaling cascade. NSCLC cell lines were treated with the EGFR tyrosine kinase inhibitor (TKI) gefitinib and PD16,8393, the AKT inhibitor SH-6 and LY294002, the farnesyltransferase inhibitor L744832, and the mTOR inhibitor rapamycin. Response was correlated to expression of AKT, p-AKT, EGFR, S6K1, p-S6K1, PTEN and to the mutation status of EGFR and KRAS. As expected, mutation of the EGFR predicted response to EGFR-TKI. The resistance mutation T790M conferred resistance to treatment with gefitinib, but not to the irreversible EGFR inhibitor PD16,8393. In cell lines independent of the EGFR, expression of PTEN correlated with resistance to AKT inhibition, EGFR expression correlated to resistance to 17-AAG and L744832 and S6K1 as well as p-S6K1 expression correlated with sensitivity to rapamycin.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Carcinoma, Non-Small-Cell Lung / drug therapy*
-
Cell Line, Tumor
-
Chromones / pharmacology
-
Drug Resistance, Neoplasm / genetics
-
Drug Screening Assays, Antitumor*
-
ErbB Receptors / antagonists & inhibitors*
-
ErbB Receptors / drug effects
-
ErbB Receptors / genetics
-
Farnesyltranstransferase / antagonists & inhibitors
-
Gefitinib
-
Humans
-
Lung Neoplasms / drug therapy*
-
MAP Kinase Signaling System / drug effects
-
Morpholines / pharmacology
-
PTEN Phosphohydrolase / antagonists & inhibitors
-
PTEN Phosphohydrolase / drug effects
-
PTEN Phosphohydrolase / metabolism
-
Phosphatidylinositols / pharmacology
-
Protein Kinase Inhibitors / pharmacology*
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
-
Proto-Oncogene Proteins c-akt / drug effects
-
Proto-Oncogene Proteins c-akt / metabolism
-
Proto-Oncogene Proteins p21(ras)
-
Quinazolines / pharmacology
-
Sirolimus / pharmacology
-
ras Proteins / genetics
Substances
-
Chromones
-
KRAS protein, human
-
Morpholines
-
PD168393
-
Phosphatidylinositols
-
Protein Kinase Inhibitors
-
Proto-Oncogene Proteins
-
Quinazolines
-
SH-6 compound
-
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
-
Farnesyltranstransferase
-
ErbB Receptors
-
Proto-Oncogene Proteins c-akt
-
PTEN Phosphohydrolase
-
PTEN protein, human
-
Proto-Oncogene Proteins p21(ras)
-
ras Proteins
-
Gefitinib
-
Sirolimus