InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma.

Ma Y, Tang N, Thompson RC, Mobley BC, Clark SW, Sarkaria JN, Wang J
Clin Cancer Res. 2016 22 (7): 1767-76

PMID: 26561558 · PMCID: PMC4818693 · DOI:10.1158/1078-0432.CCR-15-1677

PURPOSE - Aberrant activation of EGFR is a hallmark of glioblastoma. However, EGFR inhibitors exhibit at best modest efficacy in glioblastoma. This is in sharp contrast with the observations in EGFR-mutant lung cancer. We examined whether activation of functionally redundant receptor tyrosine kinases (RTKs) conferred resistance to EGFR inhibitors in glioblastoma.

EXPERIMENTAL DESIGN - We collected a panel of patient-derived glioblastoma xenograft (PDX) lines that maintained expression of wild-type or mutant EGFR in serial xenotransplantation and tissue cultures. Using this physiologically relevant platform, we tested the abilities of several RTK ligands to protect glioblastoma cells against an EGFR inhibitor, gefitinib. Based on the screening results, we further developed a combination therapy cotargeting EGFR and insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF1R).

RESULTS - Insulin and IGF1 induced significant protection against gefitinib in the majority of EGFR-dependent PDX lines with one exception that did not express InsR or IGF1R. Blockade of the InsR/IGF1R pathway synergistically improved sensitivity to gefitinib or dacomitinib. Gefitinib alone effectively attenuated EGFR activities and the downstream MEK/ERK pathway. However, repression of AKT and induction of apoptosis required concurrent inhibition of both EGFR and InsR/IGF1R. A combination of gefitinib and OSI-906, a dual InsR/IGF1R inhibitor, was more effective than either agent alone to treat subcutaneous glioblastoma xenograft tumors.

CONCLUSIONS - Our results suggest that activation of the InsR/IGF1R pathway confers resistance to EGFR inhibitors in EGFR-dependent glioblastoma through AKT regulation. Concurrent blockade of these two pathways holds promise to treat EGFR-dependent glioblastoma.

©2015 American Association for Cancer Research.

MeSH Terms (20)

Animals Antineoplastic Agents Cell Line, Tumor Disease Models, Animal Drug Resistance, Neoplasm ErbB Receptors Gefitinib Glioblastoma Humans Insulin Insulin-Like Growth Factor I Mice Protein Kinase Inhibitors Proto-Oncogene Proteins c-akt Quinazolines Receptor, IGF Type 1 Receptor, Insulin Signal Transduction Tumor Burden Xenograft Model Antitumor Assays

Connections (1)

This publication is referenced by other Labnodes entities: