1. Mechanisms of Innate and Acquired Resistance to Anti-EGFR Therapy: A Review of Current Knowledge with a Focus on Rechallenge Therapies
- Author
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Scott Kopetz, Christine Megerdichian Parseghian, Jonathan M. Loree, Stefania Napolitano, Parseghian, C. M., Napolitano, S., Loree, J. M., and Kopetz, S.
- Subjects
0301 basic medicine ,Cancer Research ,Colorectal cancer ,Protein Kinase Inhibitor ,Drug resistance ,medicine.disease_cause ,Article ,03 medical and health sciences ,Paracrine signalling ,0302 clinical medicine ,Acquired resistance ,Neoplasms ,Biomarkers, Tumor ,medicine ,Humans ,PTEN ,Molecular Targeted Therapy ,ErbB Receptor ,Protein Kinase Inhibitors ,Mutation ,biology ,business.industry ,Cancer ,medicine.disease ,ErbB Receptors ,030104 developmental biology ,Oncology ,Ectodomain ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Neoplasm ,business ,Human - Abstract
Innate and acquired resistance to anti-EGFR therapy (EGFRi) is a major limitation in the treatment of metastatic colorectal cancer (mCRC). Although RAS genes are the most commonly mutated innate and acquired oncogenes in cancer, there are a number of other mechanisms that limit the effectiveness of EGFRi. Patients with innate resistance have been found to contain BRAFV600E mutations, and possibly MET, MEK, PIK3CA, PTEN, and HER2 alterations. Meanwhile, BRAFV600E mutations may also be involved in acquired resistance to EGFRi, in addition to EGFR ectodomain mutations, MET alterations, and possibly HER2 amplification. In addition, paracrine effects and cell-fate mechanisms of resistance are being increasingly described as contributing to acquired resistance. Utilization of circulating tumor DNA has been paramount in monitoring the dynamic nature of acquired resistance and has helped to guide treatment decisions, particularly in the EGFRi rechallenge setting. Herein, we provide an in-depth review of EGFRi-resistance mechanisms and describe the current therapeutic landscape in the hopes of identifying effective rechallenge strategies.
- Published
- 2019