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Inhibition of IGF1R signaling abrogates resistance to afatinib (BIBW2992) in EGFR T790M mutant lung cancer cells. Mol Carcinog 2016 May;55(5):991-1001 PMID: 26052929 PMCID: PMC6003619

Pubmed ID

26052929

DOI

10.1002/mc.22342

Abstract

Non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) mutation have benefited from treatment of reversible EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. Acquisition of a secondary mutation in EGFR T790M is the most common mechanism of resistance to first generation EGFR TKIs, resulting in therapeutic failure. Afatinib is a second generation of EGFR TKI that showed great efficacy against tumors bearing the EGFR T790M mutation, but it failed to show the improvement on overall survival of lung cancer patients with EGFR mutations possibly because of novel acquired resistance mechanisms. Currently, there are no therapeutic options available for lung cancer patients who develop acquired resistance to afatinib. To identify novel resistance mechanism(s) to afatinib, we developed afatinib resistant cell lines from a parental human-derived NSCLC cell line, H1975, harboring both EGFR L858R and T790M mutations. We found that activation of the insulin-like growth factor 1 receptor (IGF1R) signaling pathway contributes to afatinib resistance in NSCLC cells harboring the T790M mutation. IGF1R knockdown not only significantly sensitizes resistant cells to afatinib, but also induces apoptosis in afatinib resistance cells. In addition, combination treatment with afatinib and linsitinib shows more than additive effects on tumor growth in in vivo H1975 xenograft. Therefore, these finding suggest that IGF1R inhibition or combination of EGFR-IGF1R inhibition strategies would be potential ways to prevent or potentiate the effects of current therapeutic options to lung cancer patients demonstrating resistance to either first or second generation EGFR TKIs.

Author List

Lee Y, Wang Y, James M, Jeong JH, You M

Authors

Michael James PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Yian Wang MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




Scopus

2-s2.0-84930532549   20 Citations

MESH terms used to index this publication - Major topics in bold

Animals
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Drug Resistance, Neoplasm
Drug Synergism
ErbB Receptors
Gene Expression Regulation, Neoplastic
Humans
Imidazoles
Lung Neoplasms
Mice
Mutation
Pyrazines
Quinazolines
Receptors, Somatomedin
Signal Transduction
Xenograft Model Antitumor Assays
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e