Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in EGFR-Mutant and ALK-Positive Lung Cancers

Abstract : This project has made very good progress. We have now unveiled an even larger role for defective apoptosis in the emergence of resistance. We have been very successful in our ability to generate cell lines derived from patient biopsies both before treatment and at the time of resistance. We are now using these patient-derived cell lines to assess BIM levels and apoptotic response to next-generation inhibitors. The capacity to develop cell lines from patient biopsies was published in December, 2014 in Science. We have used these models to develop effective combinations to overcome the defect in apoptosis which has led to a CTEP-sponsored clinical trial combining AZD9291 and ABT-263. Our research has expanded beyond just assessing BIM, and is also focusing on the role of a diminished apoptotic response as clones develop resistance to targeted therapies. Although BIM is one such mechanism, it is not the only one. This research has uncovered a novel, unexpected connection between EMT, low BIM, and resistance to targeted therapies. Two manuscripts (one under review at Nature Communications and one to be submitted) have been written this year describing our findings.