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Sci Signal. 2019 Aug 20;12(595). pii: eaas8779. doi: 10.1126/scisignal.aas8779.

Targeting tumor phenotypic plasticity and metabolic remodeling in adaptive cross-drug tolerance.

Author information

1
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. shiladit@mit.edu goldman1@mit.edu.
2
Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
3
Mitra Biotech, Integrative Immuno-Oncology Center, Woburn, MA 01801, USA.
4
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
5
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
6
School of Medicine, Queen's University, Kingston, ON K7L 3N6, Canada.
7
Mitra Biotech, 7, Service Road, Pragathi Nagar, Electronic City, Bengaluru, Karnataka 560100, India.
8
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
9
Medical and Biological Laboratories International, Woburn, MA 01801, USA.
10
Department of Surgical Oncology, HCG Bangalore Institute of Oncology Specialty Center, Bengaluru, Karnataka 560027, India.
11
Department of Applied Mathematics, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
12
Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
13
Dana Farber Cancer Institute, Boston, MA 02115, USA.

Abstract

Metastable phenotypic state transitions in cancer cells can lead to the development of transient adaptive resistance or tolerance to chemotherapy. Here, we report that the acquisition of a phenotype marked by increased abundance of CD44 (CD44Hi) by breast cancer cells as a tolerance response to routinely used cytotoxic drugs, such as taxanes, activated a metabolic switch that conferred tolerance against unrelated standard-of-care chemotherapeutic agents, such as anthracyclines. We characterized the sequence of molecular events that connected the induced CD44Hi phenotype to increased activity of both the glycolytic and oxidative pathways and glucose flux through the pentose phosphate pathway (PPP). When given in a specific order, a combination of taxanes, anthracyclines, and inhibitors of glucose-6-phosphate dehydrogenase (G6PD), an enzyme involved in glucose metabolism, improved survival in mouse models of breast cancer. The same sequence of the three-drug combination reduced the viability of patient breast tumor samples in an explant system. Our findings highlight a convergence between phenotypic and metabolic state transitions that confers a survival advantage to cancer cells against clinically used drug combinations. Pharmacologically targeting this convergence could overcome cross-drug tolerance and could emerge as a new paradigm in the treatment of cancer.

PMID:
31431543
DOI:
10.1126/scisignal.aas8779

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