The insulin‐like growth factor 1 receptor causes acquired resistance to erlotinib in lung cancer cells with the wild‐type epidermal growth factor receptor

Abstract

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy often provides a dramatic response in lung cancer patients with EGFR mutations. In addition, moderate clinical efficacy of the EGFR-TKI, erlotinib, has been shown in lung cancer patients with the wild-type EGFR. Numerous molecular mechanisms that cause acquired resistance to EGFR-TKIs have been identified in lung cancers with the EGFR mutations; however, few have been reported in lung cancers with the wild-type EGFR. We used H358 lung adenocarcinoma cells lacking EGFR mutations that showed modest sensitivity to erlotinib. The H358 cells acquired resistance to erlotinib via chronic exposure to the drug. The H358 erlotinib-resistant (ER) cells do not have a secondary EGFR mutation, neither MET gene amplification nor PTEN downregulation; these have been identified in lung cancers with the EGFR mutations. From comprehensive screening of receptor tyrosine kinase phosphorylation, we observed increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) in H358ER cells compared with parental H358 cells. H358ER cells responded to combined therapy with erlotinib and NVP-AEW541, an IGF1R-TKI. Our results indicate that IGF1R activation is a molecular mechanism that confers acquired resistance to erlotinib in lung cancers with the wild-type EGFR.

AXL Inhibition Sensitizes Mesenchymal Cancer Cells to Antimitotic Drugs

“…Furthermore, there may be off-target cytotoxic effects of AXL-targeted RNAi reagents. Notably, a recently reported analysis of NSCLC cells with acquired erlotinib resistance and increased AXL levels similarly excluded a functional role for AXL (34).…”

Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors

“…Furthermore, activation of members of the RAS family was shown to confer resistance to ROS1 inhibitors (39). In EGFR-mutant lung cancers, resistance to EGFR TKIs may be associated with increased dependency on RAS-MAPK signaling, including ERK activation, loss of NF1, and CRKL amplification (13,(40)(41)(42). Amplification of MAPK1 was reported as a resistance mechanism of WZ4002 and has been observed in AZD9291 (12).…”

MicroRNA let-7i induced autophagy to protect T cell from apoptosis by targeting IGF1R

“…The increasing IGF1R protected T cells from apoptosis through the transduction of Phosphoinositide 3-kinase (PI3 K)/Akt and Mitogen-activated protein kinase (MAPK) pathways [17,26]. IGF1R anti-apoptotic effects have been well documented in various tumor cells, including gastrointestinal stromal tumors [29], prostate cancer [30] and lung cancer [31], suggesting that IGF1R is closely correlated with cells survival. However, a strinking decline in IGF1R observed in this study seemed to be contradictory to the fact that numbers of T cells were required for immune response in AS [32].…”