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

摘要

The project has had very good progress over the past year. There have been a few developments that have accelerated discovery. We have been able to develop cell lines directly from patient biopsies after the development of resistance in the clinic. We had not had this capability when we applied for this award. We can now use these clinically relevant models to assess the expression of BIM and induction of apoptosis. We are also able to test new therapeutic strategies to overcome the low apoptotic rates. These studies led to the identification of the combination of ABT-263 and irreversible EGFR inhibitors to treat T790M containing EGFR mutant cancers as planned in Aim 3 of this award. The success of these studies has led to a clinical trial sponsored by CTEP combining AZD9291 and ABT263. This should enter the clinic in 2015. We have also worked hard to validate a robust, quantitative IHC method for measuring BIM. This will inform the value of this biomarker to determine which patients will benefit most from this combination.