Inhibition of IGF1R signaling abrogates resistance to afatinib (BIBW2992) in EGFR T790M mutant lung cancer cells

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

Personalized therapy for lung cancer: Striking a moving target

“…Other major tyrosine kinase parallel pathways that are being targeted for inhibition in EGFR-mutated NSCLC include HER2, IGF-1R, AXL, and FGFR3 (91)(92)(93)(94)(95). HER2 amplification, although rare in treatment-naive EGFR-mutant patients, represents up to 13% of EGFR TKI resistance and appears to be mutually exclusive from T790M (45,91).…”

Targeted therapies for treatment of non‐small cell lung cancer—Recent advances and future perspectives

“…This was attributed to inhibition of the type I insulin‐like growth factor receptor (IGF‐IR) by a metabolite of the drug. This is an interesting feature for future studies to evaluate, as activation of the IGF‐1R pathway is a proposed mechanism of cancer resistance to EGFR‐inhibitors . The ongoing TIGER trials will provide data comparing rociletinib treatment with chemotherapy or erlotinib.…”

Update on afatinib-based combination regimens for the treatment of EGFR mutation-positive non-small-cell lung cancer

“…The mechanism of action of afatinib plus EGFR antibodies remains unknown, but appears to necessitate broad ErbB inhibition as no overall responses have been observed in trials of cetuximab in combination with erlotinib or gefitinib [19,20] afatinib plus iGF-1r inhibitors IGF-1R signaling is known to play a critical role in the development and progression of various tumors, and has been implicated in acquired resistance to a variety of anticancer therapies, including EGFR-TKIs [21,22]. Although clinical studies of IGF-1R-targeted monotherapies have been largely disappointing to date, recent preclinical studies suggest that combination therapy with afatinib may help to overcome acquired resistance to EGFR-TKIs and thus potentially improve treatment outcomes in patients with EGFR mutation-positive NSCLC [23]. For example, combined treatment with an IGF-1R inhibitor and afatinib resulted in synergistic tumor growth inhibition in a mouse xenograft model of EGFR mutation-positive NSCLC.…”