American Association for Cancer Research
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Supplementary Figure 2 from Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR-Mutant Lung Cancer

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journal contribution
posted on 2023-04-03, 21:06 authored by Erin M. Tricker, Chunxiao Xu, Sharmeen Uddin, Marzia Capelletti, Dalia Ercan, Atsuko Ogino, Christine A. Pratilas, Neal Rosen, Nathanael S. Gray, Kwok-Kin Wong, Pasi A. Jänne

Supplementary Figure S2. Comparison of WZ4002 + crizotinib and WZ4002 + trametinib combinations in TKI resistant cell lines. HCC827 GR6 and HCC827 + HGF were treated with DMSO control (Media), 100 nM WZ4002, 30 nM trametinib, 100 nM crizotinib or WZ4002 combinations weekly. Positive wells were tallied weekly (mean +/- SD, n = 3 biological replicates of 60 wells each). Arrow indicates that confluence was not reached at 9 weeks.



Irreversible pyrimidine-based EGFR inhibitors, including WZ4002, selectively inhibit both EGFR-activating and EGFR inhibitor–resistant T790M mutations more potently than wild-type EGFR. Although this class of mutant-selective EGFR inhibitors is effective clinically in lung cancer patients harboring EGFRT790M, prior preclinical studies demonstrate that acquired resistance can occur through genomic alterations that activate ERK1/2 signaling. Here, we find that ERK1/2 reactivation occurs rapidly following WZ4002 treatment. Concomitant inhibition of ERK1/2 by the MEK inhibitor trametinib prevents ERK1/2 reactivation, enhances WZ4002-induced apoptosis, and inhibits the emergence of resistance in WZ4002-sensitive models known to acquire resistance via both T790M-dependent and T790M-independent mechanisms. Resistance to WZ4002 in combination with trametinib eventually emerges due to AKT/mTOR reactivation. These data suggest that initial cotargeting of EGFR and MEK could significantly impede the development of acquired resistance in EGFR-mutant lung cancer.Significance: Patients with EGFR-mutant lung cancer develop acquired resistance to EGFR and mutant-selective EGFR tyrosine kinase inhibitors. Here, we show that cotargeting EGFR and MEK can prevent the emergence of a broad variety of drug resistance mechanisms in vitro and in vivo and may be a superior therapeutic regimen for these patients. Cancer Discov; 5(9); 960–71. ©2015 AACR.This article is highlighted in the In This Issue feature, p. 893