Combined EGFR/MEK inhibition prevents the emergence of resistance in EGFR-mutant lung cancer Journal Article
| Authors: | Tricker, E. M.; Xu, C.; Uddin, S.; Capelletti, M.; Ercan, D.; Ogino, A.; Pratilas, C. A.; Rosen, N.; Gray, N. S.; Wong, K. K.; Jänne, P. A. |
| Article Title: | Combined EGFR/MEK inhibition prevents the emergence of resistance in EGFR-mutant lung cancer |
| Abstract: | 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. © 2015 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 5 |
| Issue: | 9 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2015-09-01 |
| Start Page: | 960 |
| End Page: | 971 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-15-0063 |
| PROVIDER: | scopus |
| PUBMED: | 26036643 |
| PMCID: | PMC4824006 |
| DOI/URL: | |
| Notes: | Export Date: 2 October 2015 -- Source: Scopus |
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