GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

Wu, Q.; Alawi, W.; Deblois, G.; Cruickshank, J.; Duan, S.; Fernandes, E. L.; Haight, J.; Tonekaboni, S. A.; Fortier, A.; Kuasne, H.; McKee, T.; Mahmoud, H.; Cameron, S.; Artun, N. D.; Chen, W.; Vellanki, R.; Zhou, S.; Done, S. J.; Park, M.; Cescon, D.; Kains, B. H.; Lupien, M.; Arrowsmith, C. H.

doi:10.1101/764944

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bioRxiv · 10.1101/764944

GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

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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 implicates E2F Targets pathway activity as a surrogate of OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) are strongly correlated 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.

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Wu, Q., Alawi, W., Deblois, G., Cruickshank, J., Duan, S., Fernandes, E. L., Haight, J., Tonekaboni, S. A., Fortier, A., Kuasne, H., McKee, T., Mahmoud, H., Cameron, S., Artun, N. D., Chen, W., Vellanki, R., Zhou, S., Done, S. J., Park, M., Cescon, D., Kains, B. H., Lupien, M., Arrowsmith, C. H.. 2019-09-11. GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer. https://doi.org/10.1101/764944

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