Therapeutic Strategies Utilized in the Setting of Acquired Resistance to EGFR Tyrosine Kinase Inhibitors

1. Helena A. Yu1,*,
2. Gregory J. Riely1, and
3. Christine M. Lovly2,*

+ Author Affiliations

1. ¹Department of Medicine, Memorial Sloan Kettering Cancer Center, Weil Cornell Medical College, New York, New York.
2. ²Department of Medicine, Vanderbilt University School of Medicine and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.

1. ↵*Corresponding Authors:
   Christine M. Lovly, Department of Medicine and Cancer Biology, Vanderbilt University School of Medicine and Vanderbilt Ingram Cancer Center, Nashville, TN 37232-6307. Phone: 615-936-3457; Fax: 615-343-2973; E-mail: christine.lovly@vanderbilt.edu; and Helena A. Yu, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weil Cornell Medical College, New York, NY10065. Phone 646-888-4274; fax 646-888-4263; E-mail: YuH@mskcc.org

Abstract

Patients with EGFR-mutant lung cancer derive significant therapeutic benefit from treatment with EGFR tyrosine kinase inhibitors (TKI). Unfortunately, acquired resistance is an inevitable consequence of this treatment strategy, with a broad variety of resistance mechanisms including acquired EGFR mutations (e.g., T790M) and activation of bypass signaling pathways, such as MET and HER2. Several therapeutic strategies hypothesized to delay or overcome resistance have been tested in clinical trials, including “next-generation” EGFR TKIs and rational combinations of targeted agents. However, to date, there are no FDA-approved therapies for patients with acquired resistance to first-line EGFR TKI therapy. There remains a critical need for more effective and better tailored treatments in this setting to match treatments to the individual patient and specific resistance mechanism at hand. In this review, we discuss known mechanisms of resistance to first-line EGFR TKI therapy and describe previous and ongoing strategies to overcome resistance. 

Clin Cancer Res; 20(23); 5898–907. ©2014 AACR.