IGF2 Autocrine-Mediated IGF1R Activation Is a Clinically Relevant Mechanism of Osimertinib Resistance in Lung Cancer.

Tadashi Manabe,Katsuhisa Horimoto,Ichiro Kawada,Shinnosuke Ikemura,Junko Hamamoto,Kazuhiko Fukui,Kenzo Soejima,Hiroyuki Yasuda,Hideki Terai,Koichi Fukunaga,Toshiki Ebisudani,Harumi Kagiwada,Yuichiro Hayashi,Keigo Kobayashi,Keita Masuzawa

doi:10.1158/1541-7786.mcr-19-0956

Abstract

EGFR-mutated lung cancer accounts for a significant proportion of lung cancer cases worldwide. For these cases, osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is extensively used as a first-line or second-line treatment. However, lung cancer cells acquire resistance to osimertinib in 1 to 2 years. Thus, a thorough clarification of resistance mechanisms to osimertinib is highly anticipated. Recent next-generation sequencing (NGS) of lung cancer samples identified several genetically defined resistance mechanisms to osimertinib, such as EGFR C797S or MET amplification. However, nongenetically defined mechanisms are not well evaluated. For a thorough clarification of osimertinib resistance, both genetic and nongenetic mechanisms are essential. By using our comprehensive protein phosphorylation array, we detected IGF1R bypass pathway activation after EGFR abolishment. Both of our established lung cancer cells and patient-derived lung cancer cells demonstrated IGF2 autocrine-mediated IGF1R pathway activation as a mechanism of osimertinib resistance. Notably, this resistance mechanism was not detected by a previously performed NGS, highlighting the essential roles of living cancer cells for a thorough clarification of resistance mechanisms. Interestingly, the immunohistochemical analysis confirmed the increased IGF2 expression in lung cancer patients who were treated with osimertinib and met the established clinical definition of acquired resistance. The findings highlight the crucial roles of cell-autonomous ligand expression in osimertinib resistance. Here, we report for the first time the IGF2 autocrine-mediated IGF1R activation as a nongenetic mechanism of osimertinib resistance in lung cancer at a clinically relevant level. IMPLICATIONS: Using comprehensive protein phosphorylation array and patient-derived lung cancer cells, we found that IGF2 autocrine-mediated IGF1R pathway activation is a clinically relevant and common mechanism of acquired resistance to osimertinib.

Highlights

In non–small cell lung cancer (NSCLC), somatic mutations in the tyrosine kinase domain of EGFR have been identified in a significant subgroup of patients [1,2,3]
Implications: Using comprehensive protein phosphorylation array and patient-derived lung cancer cells, we found that IGF2 autocrinemediated IGF1R pathway activation is a clinically relevant and common mechanism of acquired resistance to osimertinib
RTK inhibitors, which suppress the detected pathways, inhibited the proliferation of erlotinib treated PC9 cells, indicating that the “p-Y-IRS1 p-IRS2 bind PI3K” and “VEGFR2mediated vascular permeability B” pathways contribute to the resistance to EGFR-TKI in PC9 cells

Summary

Introduction

In non–small cell lung cancer (NSCLC), somatic mutations in the tyrosine kinase domain of EGFR have been identified in a significant subgroup of patients [1,2,3]. Somatic mutations in the EGFR tyrosine kinase domain activate EGFR by promoting its active conformation [4,5,6,7]. EGFR-mutated lung cancer cells are dependent on activated EGFR signaling for their survival and proliferation [8, 9]. Multiple EGFR tyrosine kinase inhibitors have been developed (first generation: gefitinib and erlotinib; second generation: afatinib and dacomitinib; and third generation: osimertinib and rociletinib) to target EGFR signals in NSCLC. Multiple clinical trials involving EGFR-TKIs have demonstrated significant. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/)

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