title: Therapeutic strategies utilized in the setting of acquired resistance to EGFR tyrosine kinase inhibitors.
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.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weil Cornell Medical College, New York, New York. christine.lovly@vanderbilt.edu YuH@mskcc.org.
authors.forename: Helena A
authors.initials: HA
authors.lastname: Yu
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weil Cornell Medical College, New York, New York.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine and Vanderbilt Ingram Cancer Center, Nashville, Tennessee. christine.lovly@vanderbilt.edu YuH@mskcc.org.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lovly
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors