Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway Journal Article

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Authors: Cortot, A. B.; Repellin, C. E.; Shimamura, T; Capelletti, M.; Zejnullahu, K.; Ercan, D.; Christensen, J. G.; Wong, K. K.; Gray, N. S.; Janne, P. A.
Article Title: Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway
Abstract: The clinical efficacy of EGF receptor (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 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 nor WZ4002-resistant clones of PC9 harbor EGFR T790M. Instead, they have shown activated insulin-like growth factor receptor (IGF1R) signaling as a result of loss of expression of IGFBP3 with the IGF1R inhibitor, BMS 536924, restoring EGFR inhibitor sensitivity. Intriguingly, prolonged exposure to either PF299804 or WZ4002 results in the emergence of a more drug-resistant subclone that exhibits ERK activation. A MEK inhibitor, CI-1040, partially restores sensitivity to the 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 non-small cell lung cancer. However, multiple drug resistance mechanisms can still emerge. Preventing the emergence of drug resistance, by targeting pathways that become activated in resistant cancers, may be a more effective clinical strategy.
Journal Title: Cancer research
Volume: 73
Issue: 2
ISSN: 1538-7445; 0008-5472
Publisher: AACR  
Journal Place: United States
Date Published: 2013
Start Page: 834
End Page: 843
Language: eng
DOI/URL:

10.1158/0008-5472.CAN-12-2066
Notes: LR: 20150404; GR: P50 CA090578/CA/NCI NIH HHS/United States; GR: P50CA090578/CA/NCI NIH HHS/United States; GR: R01 CA114465/CA/NCI NIH HHS/United States; GR: R01 CA135257/CA/NCI NIH HHS/United States; GR: R01CA114465/CA/NCI NIH HHS/United States; GR: R01CA135257/CA/NCI NIH HHS/United States; JID: 2984705R; 0 (Acrylamides); 0 (PF 00299804); 0 (Protein Kinase Inhibitors); 0 (Pyrimidines); 0 (Quinazolinones); 0 (WZ4002); EC 2.7.10.1 (Receptor, IGF Type 1); NIHMS568075; OID: NLM: NIHMS568075; OID: NLM: PMC3994895; 2012/11/19 [aheadofprint]; 2013/01/10 [aheadofprint]; ppublish