GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer

Qin Wu; Wail Ba-Alawi; Genevieve Deblois; Jennifer Cruickshank; Shili Duan; Evelyne Lima-Fernandes; Jillian Haight; Seyed Ali Madani Tonekaboni; Anne-Marie Fortier; Hellen Kuasne; Trevor D McKee; Hassan Mahmoud; Michelle Kushida; Sarina Cameron; Nergiz Dogan-Artun; WenJun Chen; Yan Nie; Lan Xin Zhang; Ravi N Vellanki; Stanley Zhou; Panagiotis Prinos; Bradly G Wouters; Peter B Dirks; Susan J Done; Morag Park; David W Cescon; Benjamin Haibe-Kains; Mathieu Lupien; Cheryl H Arrowsmith

doi:10.1038/s41467-020-18020-8

GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer

Nat Commun. 2020 Aug 21;11(1):4205. doi: 10.1038/s41467-020-18020-8.

Authors

Qin Wu^#^{1

2

3}, Wail Ba-Alawi^#^{2

3}, Genevieve Deblois², Jennifer Cruickshank⁴, Shili Duan², Evelyne Lima-Fernandes^{1

2}, Jillian Haight⁴, Seyed Ali Madani Tonekaboni^{2

3}, Anne-Marie Fortier⁵, Hellen Kuasne⁵, Trevor D McKee^{2

6}, Hassan Mahmoud^{2

3

7}, Michelle Kushida⁸, Sarina Cameron^{2

3}, Nergiz Dogan-Artun^{2

3}, WenJun Chen¹, Yan Nie^{1

2

3}, Lan Xin Zhang¹, Ravi N Vellanki², Stanley Zhou^{2

3}, Panagiotis Prinos¹, Bradly G Wouters^{2

3}, Peter B Dirks^{8

9

10}, Susan J Done⁴, Morag Park⁵, David W Cescon⁴, Benjamin Haibe-Kains^{2

3

11

12

13}, Mathieu Lupien^{14

15

16}, Cheryl H Arrowsmith^{17

18

19}

Affiliations

¹ Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
² Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada.
³ Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada.
⁴ The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada.
⁵ Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada.
⁶ Princess Margaret Cancer Centre, STTARR Innovation Facility, Toronto, ON, Canada.
⁷ Faculty of Computer and Informatics, Benha University, Benha, Egypt.
⁸ Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain tumor Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.
⁹ Division of Neurosurgery, University of Toronto, Toronto, ON, M5S 1A8, Canada.
¹⁰ Departments of Molecular Genetics and Surgery, University of Toronto, Toronto, ON, M5S1A8, Canada.
¹¹ Department of Computer Science, University of Toronto, Toronto, M5T 3A1, ON, Canada.
¹² Ontario Institue for Cancer Research, Toronto, M5G 2M9, ON, Canada.
¹³ Vector Institute for Artificial Intelligence, Toronto, ON, Canada.
¹⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada. Mathieu.Lupien@uhnresearch.ca.
¹⁵ Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada. Mathieu.Lupien@uhnresearch.ca.
¹⁶ Ontario Institue for Cancer Research, Toronto, M5G 2M9, ON, Canada. Mathieu.Lupien@uhnresearch.ca.
¹⁷ Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada. Cheryl.Arrowsmith@uhnresearch.ca.
¹⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada. Cheryl.Arrowsmith@uhnresearch.ca.
¹⁹ Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada. Cheryl.Arrowsmith@uhnresearch.ca.

^# Contributed equally.

Abstract

Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data suggests that the functionality of the E2F pathway may reflect to some extent OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) strongly correlate with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Biomarkers, Tumor
Breast Neoplasms / metabolism
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Female
Gene Expression Regulation, Neoplastic / drug effects
Glucose Transporter Type 1 / antagonists & inhibitors*
Glucose Transporter Type 1 / genetics
Glucose Transporter Type 1 / metabolism*
Humans
Mice
Oxidative Phosphorylation
Proteomics
Pyrazoles / pharmacology
Pyridines / pharmacology
Quinolines
RNA, Messenger / metabolism
Retinoblastoma Binding Proteins / metabolism*
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / metabolism*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*

Substances

BAY-876
Biomarkers, Tumor
Glucose Transporter Type 1
Pyrazoles
Pyridines
Quinolines
RB1 protein, human
RNA, Messenger
Retinoblastoma Binding Proteins
SLC2A1 protein, human
STF-31
Ubiquitin-Protein Ligases

Grants and funding

WT_/Wellcome Trust/United Kingdom