Synthetic lethal combination targeting BET uncovered intrinsic susceptibility of TNBC to ferroptosis

August 21, 2020

Nandini Verma, Yaron Vinik, Ashish Saroha, Nishanth Ulhas Nair, Eytan Ruppin, Gordon Mills, Thomas Karn, Vinay Dubey, Lohit Khera, Harsha Raj, Flavio Maina, Sima Lev

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.

Read the full publication in Science Advances