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.
Highlights
During the last decade, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) established a remarkable therapeutic benefit in the patients with advanced non small cell lung cancer (NSCLC) harboring EGFR activating mutations [1,2,3,4,5,6,7]
Using Fluorescent in situ hybridization (FISH), we observed increased amplification of EGFR genes in PC-9/GR (H) cells compared with PC-9 or PC-9/GR (L) cells (Figure 1D).Taken together, these findings indicate that the increase in T790M allele frequency by gene amplification leads to more potent resistance to EGFR-TKIs
As all resistant cells were still EGFR dependent, we evaluated the efficacy of afatinib in these resistant cells
Summary
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) established a remarkable therapeutic benefit in the patients with advanced non small cell lung cancer (NSCLC) harboring EGFR activating mutations [1,2,3,4,5,6,7]. Www.impactjournals.com/oncotarget effectively inhibited T790M-containing cell lines in several preclinical models at high concentration and showed modest clinical potency, they eventually failed to prove universal clinical benefit [12,13,14,15,16] This unmet need led to the development of mutant-selective, 3rdgeneration EGFR TKIs, which comprises the irreversible pyrimidine-based WZ4002 and newer compounds of AZD9291, CO-1686, and HM61713 [17]. Considering this successive development of acquired resistance beyond T790M, monotherapy with 3rd-generation EGFR-TKIs would be insufficient to control the disease Facing these concerns, efforts to discover the mechanisms of novel acquired resistance have been increasingly made in recent studies, which addressed insulin-like growth factor receptor (IGF1R) [24] and extracellular signal-regulated kinase (ERK) signaling [25] as potential mediators of acquired resistance to WZ4002. These investigations suggest the significance of combination treatment strategies in the backbone of EGFR-TKIs to more efficiently manage the acquired resistance, and further prevent and predict the emergence of novel resistance [24,25,26,27]
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