American Association for Cancer Research
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Supplementary Figure 1 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 S1. Trametinib sensitivity of EGFR mutant NSCLC cell lines and inhibition of ERK dependent genes. (A) Inhibition of ERK1/2 was assessed in each cell line after 8 hours of treatment followed by immunoblot for total and phosphorylated ERK1/2. Hsp90 was used as a loading control. (B) The viability of PC9, HCC4006, HCC2279 and HCC2935 cells was assessed after 72 hours. (C) PC9 GR4 (EGFR Del746_A750/T790M) cells were treated with DMSO (Media), 100 nM WZ4002, 30 nM trametinib or a combination thereof for 8 hours or (D) 24 hours and ERK1/2 dependent gene transcription was assessed by quantitative PCR, asterisk, p < 0.05 by one-tailed t-test.



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