InsR/IGF1R pathway mediates resistance to EGFR inhibitors in glioblastoma

Yufang Ma, Nan Tang, Reid C. Thompson, Bret C. Mobley, Steven W. Clark, Jann N. Sarkaria, Jialiang Wang

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

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 EGFRdependent glioblastoma through AKT regulation. Concurrent blockade of these two pathways holds promise to treat EGFRdependent glioblastoma.

Original languageEnglish (US)
Pages (from-to)1767-1776
Number of pages10
JournalClinical Cancer Research
Volume22
Issue number7
DOIs
StatePublished - Apr 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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