Research Summary: Determining mechanisms of resistance to next-generation EGFR inhibitors

Grant Recipient: Dr. Lecia V. Sequist
Title of Project: Determining mechanisms of resistance to next-generation EGFR inhibitors
Sponsoring Institution:
Massachusetts General Hospital (The General Hospital Corp.), Boston, MA

One of the biggest advances in lung cancer therapy has been the development of genotype-directed therapy, where patients can be tested to see which genes are the most active in their cancers and then targeted pills can be given to shut down the messages sent from those genes. This type of treatment has been extremely successful for lung cancer patients whose cancers are EGFR mutation; however, resistance to the EGFR targeted therapy develops after about one year. The focus of our research is how drug resistance occurs and how to prevent it.

Our group at Mass General has led a large effort to understand how cancers become resistant to anti-EGFR therapy by biopsying patients who have become drug resistant and testing their tumors with real-time molecular and genetic analyses to tell us what is driving cancer growth. Our research proposal extends this work broader and deeper, looking at the mechanisms of drug resistance to the newest EGFR therapies currently entering the clinic with a next-generation deep sequencing platform. In addition, we will derive individual, patient-specific laboratory models of the resistant cancers from the material gathered at the biopsy. These models will facilitate functional research into the biology of the resistant cancers and screening with broad panels of targeted therapies to inform doctors what the best therapy options may be for an individual patient in their practice.

Our patient-oriented study will leverage bi-directional knowledge exchange between the bench and the bedside and across institutions to gain insight into how lung cancers acquire resistance to the next generation of EGFR therapies, in turn directing patients to the most appropriate treatment strategy to overcome resistance.