TY - JOUR
T1 - Synthetic lethal combination targeting BET uncovered intrinsic susceptibility of TNBC to ferroptosis
AU - Verma, Nandini
AU - Vinik, Yaron
AU - Saroha, Ashish
AU - Nair, Nishanth Ulhas
AU - Ruppin, Eytan
AU - Mills, Gordon
AU - Karn, Thomas
AU - Dubey, Vinay
AU - Khera, Lohit
AU - Raj, Harsha
AU - Maina, Flavio
AU - Lev, Sima
N1 - Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
PY - 2020/8
Y1 - 2020/8
N2 - Identification of targeted therapies for TNBC is an urgent medical need. Using a drug combination screen reliant on synthetic lethal interactions, we identified clinically relevant combination therapies for different TNBC subtypes. Two drug combinations targeting the BET family were further explored. The first, targeting BET and CXCR2, is specific for mesenchymal TNBC and induces apoptosis, whereas the second, targeting BET and the proteasome, is effective for major TNBC subtypes and triggers ferroptosis. Ferroptosis was induced at low drug doses and was associated with increased cellular iron and decreased glutathione levels, concomitant with reduced levels of GPX4 and key glutathione biosynthesis genes. Further functional studies, analysis of clinical datasets and breast cancer specimens revealed a unique vulnerability of TNBC to ferroptosis inducers, enrichment of ferroptosis gene signature, and differential expression of key proteins that increase labile iron and decrease glutathione levels. This study identified potent combination therapies for TNBC and unveiled ferroptosis as a promising therapeutic strategy.
AB - Identification of targeted therapies for TNBC is an urgent medical need. Using a drug combination screen reliant on synthetic lethal interactions, we identified clinically relevant combination therapies for different TNBC subtypes. Two drug combinations targeting the BET family were further explored. The first, targeting BET and CXCR2, is specific for mesenchymal TNBC and induces apoptosis, whereas the second, targeting BET and the proteasome, is effective for major TNBC subtypes and triggers ferroptosis. Ferroptosis was induced at low drug doses and was associated with increased cellular iron and decreased glutathione levels, concomitant with reduced levels of GPX4 and key glutathione biosynthesis genes. Further functional studies, analysis of clinical datasets and breast cancer specimens revealed a unique vulnerability of TNBC to ferroptosis inducers, enrichment of ferroptosis gene signature, and differential expression of key proteins that increase labile iron and decrease glutathione levels. This study identified potent combination therapies for TNBC and unveiled ferroptosis as a promising therapeutic strategy.
UR - http://www.scopus.com/inward/record.url?scp=85091129242&partnerID=8YFLogxK
U2 - 10.1126/sciadv.aba8968
DO - 10.1126/sciadv.aba8968
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C2 - 32937365
AN - SCOPUS:85091129242
SN - 2375-2548
VL - 6
JO - Science advances
JF - Science advances
IS - 34
M1 - eaba8968
ER -
