Journal
NATURE MEDICINE
Volume 22, Issue 3, Pages 262-269Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4040
Keywords
-
Funding
- US National Institutes of Health (NIH) [R01CA137008]
- Department of Defense
- LunGevity
- Uniting Against Lung Cancer
- Conquer Cancer Foundation of the American Society of Clinical Oncology
- Lung Cancer Research Foundation
- Targeting a Cure for Lung Cancer
- Be a Piece of the Solution
- John and Carol Barry Foundation
Ask authors/readers for more resources
Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non -small -cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR(T79OM) gatekeeper mutation can occur either by selectiori of pre-existing EGFR(T79M)-positive clones or via genetic evolution of initially EGFR(T790M)-negative drug -tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug -tolerant cells had a diminished apoptotic response to third generation EGFR inhibitors that target EGFR(T790M); treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor -resistant patient tumors. These findings provide evidence that clinically relevant drug -resistant cancer cells can both pre-exist and evolve from drug -tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available