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Nat Med. 2016 Mar;22(3):262-9. doi: 10.1038/nm.4040. Epub 2016 Feb 1.

Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition.

Author information

1
Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA.
2
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
3
Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA.
4
Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
5
Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
6
Department of Oncology, University of Torino, Torino, Italy.
7
Candiolo Cancer Institute-Fondazione Piemontese per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
8
Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
9
Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
10
Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
11
Virginia Commonwealth University Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry, Richmond, Virginia, USA.
12
Virginia Commonwealth University Massey Cancer Center, Richmond, Virginia, USA.

Abstract

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(T790M) gatekeeper mutation can occur either by selection of pre-existing EGFR(T790M)-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.

Comment in

PMID:
26828195
PMCID:
PMC4900892
DOI:
10.1038/nm.4040
[Indexed for MEDLINE]
Free PMC Article
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