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
Nature Communications 2020 August 21, 11 (1): 4205
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.

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