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Cancer Discov. 2015 Sep;5(9):960-971. doi: 10.1158/2159-8290.CD-15-0063. Epub 2015 Jun 2.

Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR-Mutant Lung Cancer.

Author information

1
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
3
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA.
4
Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA.
5
Department of Medicine, Memorial Sloane Kettering Cancer Center, New York, New York, 10065, USA.
6
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
7
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
8
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
9
Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, 20115, USA.
#
Contributed equally

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 EGFR(T790M), 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.

PMID:
26036643
PMCID:
PMC4824006
DOI:
10.1158/2159-8290.CD-15-0063
[Indexed for MEDLINE]
Free PMC Article

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