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Series GSE38404 Query DataSets for GSE38404
Status Public on Oct 01, 2012
Title Resistance to Irreversible EGFR Tyrosine Kinase Inhibitors through a Multistep Mechanism Involving the IGF1R Pathway
Organism Homo sapiens
Experiment type Expression profiling by array
Summary The clinical efficacy of EGFR kinase inhibitors gefitinib and erlotinib is limited by the development of drug resistance. The most common mechanism of drug resistance is the secondary EGFR T790M mutation. Strategies to overcome EGFR T790M mediated drug resistance include the use of mutant selective EGFR inhibitors, including WZ4002, or by the use of high concentrations of irreversible quinazoline EGFR inhibitors such as PF299804. In the current study we develop drug resistant versions of the EGFR mutant PC9 cell line which reproducibly develops EGFR T790M as a mechanism of drug resistance to gefitinib. Neither PF299804 resistant (PFR) or WZ4002 resistant (WZR) clones of PC9 harbor EGFR T790M. Instead, they demonstrate activated IGF1R signaling as a result of loss of expression of IGFBP3 and the IGF1R inhibitor, BMS 536924, restores EGFR inhibitor sensitivity. Intriguingly, prolonged exposure to either PF299804 or WZ4002 results in the emergence of a more drug resistant subclone which contains ERK activation. A MEK inhibitor, CI-1040, partially restores sensitivity to EGFR/IGF1R inhibitor combination. Moreover, an IGF1R or MEK inhibitor used in combination with either PF299804 or WZ4002 completely prevents the emergence of drug resistant clones in this model system. Our studies suggest that more effective means of inhibiting EGFR T790M will prevent the emergence of this common drug resistance mechanism in EGFR mutant NSCLC. However, multiple drug resistance mechanisms can still emerge. Preventing the emergence of drug resistance, by targeting pathways activated in resistant cancers before they emerge, may be a more effective clinical strategy.
Overall design Total of three samples with duplicate or triplicate each were analyzed.
Contributor(s) Jänne PA
Citation(s) 23172312
Submission date Jun 01, 2012
Last update date Dec 06, 2018
Contact name Pasi Janne
Organization name Dana-Farber Cancer Institute
Department Medical Oncology
Street address 44 Binney Street Dana 820
City Boston
State/province MA
ZIP/Postal code 02115
Country USA
Platforms (1)
GPL571 [HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array
Samples (8)
GSM941549 PC9_1_rep1
GSM941550 PC9_1_rep2
GSM941551 PFR31_1_rep1
BioProject PRJNA167817

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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE38404_RAW.tar 17.3 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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