Combined EGFR/MEK inhibition prevents the emergence of resistance in EGFR-mutant lung cancer

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)960-971
Number of pages12
JournalCancer discovery
Volume5
Issue number9
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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