RT Journal Article
SR Electronic
T1 GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 764944
DO 10.1101/764944
A1 Qin Wu
A1 Wail ba-alawi
A1 Genevieve Deblois
A1 Jennifer Cruickshank
A1 Shili Duan
A1 Evelyne Lima-Fernandes
A1 Jillian Haight
A1 Seyed Ali Madani Tonekaboni
A1 Anne-Marie Fortier
A1 Hellen Kuasne
A1 Trevor D. McKee
A1 Hassan Mahmoud
A1 Sarina Cameron
A1 Nergiz Dogan-Artun
A1 WenJun Chen
A1 Ravi N. Vellanki
A1 Stanley Zhou
A1 Susan J. Done
A1 Morag Park
A1 David W. Cescon
A1 Benjamin Haibe-Kains
A1 Mathieu Lupien
A1 Cheryl H. Arrowsmith
YR 2019
UL http://biorxiv.org/content/early/2019/09/11/764944.abstract
AB 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.