title: Activation of the IGF1R pathway potentially mediates acquired resistance to mutant-selective 3rd-generation EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer.
abstract: Mutant-selective, 3rd-generation EGFR-TKIs were recently developed to control lung cancer cells harboring T790M-mediated resistance. However, the development of resistance to these novel drugs seems inevitable. Thus, we investigated the mechanism of acquired resistance to the mutant-selective EGFR-TKI WZ4002. We established five WZ4002-resistant cells, derived from cells harboring both EGFR and T790M mutations by long-term exposure to increasing doses of WZ4002. Compared with the parental cells, all resistant cells showed 10-100-folds higher resistance to WZ4002, as well as cross-resistance to other mutant-selective inhibitors. Among them, three resistant cells (HCC827/WR, PC-9/WR and H1975/WR) showed dependency on EGFR signaling, but two other cells (PC-9/GR/WR and PC-9/ER/WR) were not. Notably, insulin-like growth factor-1 receptor (IGF1R) was aberrantly activated in PC-9/GR/WR cells in phospho-receptor tyrosine kinase array, consistently accompanied by loss of IGF binding protein-3 (IGFBP3). Down-regulation of IGF1R by shRNA, as well as inhibition of IGF1R activity either by AG-1024 (a small molecule IGF1R inhibitor) or BI 836845 (a monoclonal anti-IGF1/2 blocking antibody), restored the sensitivity to WZ4002 both in vitro and xenograft. Taken together, these results suggest that activation of the IGF1R pathway associated with IGFBP3 loss can induce an acquired resistance to the mutant-selective EGFR-TKI, WZ4002. Therefore, a combined therapy of IGF1R inhibitors and mutant-selective EGFR-TKIs might be a viable treatment strategy for overcoming acquired resistance.
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.|Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Yun Jung
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.|Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Seon Ye
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.|Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.|Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Ki Jung
authors.initials: KJ
authors.lastname: Sung
authors.affiliation: Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Sojung
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Woo Sung
authors.initials: WS
authors.lastname: Kim
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Joon Seon
authors.initials: JS
authors.lastname: Song
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.|Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Choi
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.|Department of Convergence Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Sung
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.|Department of Convergence Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Rho
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Jae Cheol
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000597236:IGF1R protein, human; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D047428:Protein Kinase Inhibitors; D017451:Receptors, Somatomedin; C512478:EGFR protein, human; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1
keywords: 3rd-generation; EGFR-TKI; IGF1R; NSCLC; resistance