TY - JOUR
T1 - Oxidative phosphorylation is a metabolic vulnerability in chemotherapy-resistant triple-negative breast cancer
AU - Evans, Kurt W.
AU - Yuca, Erkan
AU - Scott, Stephen S.
AU - Zhao, Ming
AU - Arango, Natalia Paez
AU - Cruz Pico, Christian X.
AU - Saridogan, Turcin
AU - Shariati, Maryam
AU - Class, Caleb Andrew
AU - Bristow, Christopher A.
AU - Vellano, Christopher P.
AU - Zheng, Xiaofeng
AU - Gonzalez-Angulo, Ana Maria
AU - Su, Xiaoping
AU - Tapia, Coya
AU - Chen, Ken
AU - Akcakanat, Argun
AU - Lim, Bora
AU - Tripathy, Debu
AU - Yap, Timothy A.
AU - Di Francesco, Maria Emilia
AU - Draetta, Giulio F.
AU - Jones, Philip
AU - Heffernan, Timothy P.
AU - Marszalek, Joseph R.
AU - Meric-Bernstam, Funda
N1 - Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research
PY - 2021/11/1
Y1 - 2021/11/1
N2 - Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pretreatment biopsies from patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of OXPHOS signature. IACS-10759, a novel inhibitor of OXPHOS, stabilized growth in multiple TNBC patient-derived xenografts (PDX). On gene expression profiling, all of the sensitive models displayed a basal-like 1 TNBC subtype. Expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen to identify synthetic lethal targets in tumors treated with IACS-10759 found several potential targets, including CDK4. We validated the antitumor efficacy of the combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 in vitro and in vivo. In addition, the combination of IACS-10759 and multi-kinase inhibitor cabozantinib had improved antitumor efficacy. Taken together, our data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens.
AB - Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pretreatment biopsies from patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of OXPHOS signature. IACS-10759, a novel inhibitor of OXPHOS, stabilized growth in multiple TNBC patient-derived xenografts (PDX). On gene expression profiling, all of the sensitive models displayed a basal-like 1 TNBC subtype. Expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen to identify synthetic lethal targets in tumors treated with IACS-10759 found several potential targets, including CDK4. We validated the antitumor efficacy of the combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 in vitro and in vivo. In addition, the combination of IACS-10759 and multi-kinase inhibitor cabozantinib had improved antitumor efficacy. Taken together, our data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens.
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U2 - 10.1158/0008-5472.CAN-20-3242
DO - 10.1158/0008-5472.CAN-20-3242
M3 - Article
C2 - 34518211
AN - SCOPUS:85119022171
SN - 0008-5472
VL - 81
SP - 5572
EP - 5581
JO - Cancer Research
JF - Cancer Research
IS - 21
ER -