Posted March 31, 2015
Jeffrey Engelman, M.D., Ph.D., and Lecia Sequist, M.D., Ph.D., Massachusetts General Hospital, Boston, Massachusetts

Drs. Engelman and Sequist Targeted cancer therapies have benefited many lung cancer patients; however, most tumors acquire resistance to these drugs. Drs. Engelman and Sequist, physician research scientists at the Massachusetts General Hospital, are dedicated to understanding how drug resistance develops in lung cancer patients, with the aim of improving patients' response to treatment. With funding from a Fiscal Year 2012 LCRP Translational Research Partnership Award, the investigators are seeking to establish BIM as a biomarker that indicates whether a tumor is likely to respond to targeted treatment or not and have begun work on alternative therapies to improve treatment outcomes based on this hypothesis.

Drs. Engelman, Sequist, and colleagues began this work by establishing several drug-resistant cancer cell lines from the tumors of individual lung cancer patients after resistance had developed. These cell lines were then subjected to genetic and molecular analyses to confirm the presence of a biomarker indicating the patient's likelihood to respond to treatment. Specifically, Dr. Engleman successfully identified drug combinations that enhanced apoptosis in drug-resistant tumor cells in vitro and in vivo. In particular, combinations with navitoclax (a BCL-2/BCL-XL inhibitor) helped overcome resistance in multiple models. These findings underscore the power of enhancing the apoptotic response in resistant cancers.

Results from this study, and others like it, are key to identifying drug combinations that can mediate therapy resistance and are suitable for clinical trials. Based on his success with the patient-derived resistant lung cancer cell lines in this study and other unpublished work, Dr. Engelman is facilitating an upcoming clinical trial that will investigate the effectiveness of navitoclax (BCL-2 inhibitor) in combination with irreversible EGFR inhibitors in treating lung cancers harboring T790M EGFR mutations. The investigators hope that the results of these studies will permit the discovery and evaluation of therapeutic targets for drug-resistant cancers in specific patient populations.


Crystal AS, Shaw AT, Sequist LV, et al. 2014. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science 346(6216):1480-1486. .

Press Releases:

Mass General researchers find that direct drug screening of patient biopsies could overcome resistance to targeted therapy.

Direct drug screening of patient biopsies could overcome resistance to targeted therapy.


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

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