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

Abstract

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.

Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance

“…This result was consistent with Western blots analysis showing a strong increase in Caspase3 and PARP cleavage upon combined BCL‐XL+WEE1 inhibition (Figure 7a). By contrast, inhibition of ferroptosis, another cell death mechanism to which TNBC cells are highly sensitive, [ 51 ] did not prevent cell death (Figure 8e,f). Together, these findings indicate that the combined targeting of BCL‐XL and WEE1 exacerbates the dependency of TNBC cells on WEE1 function in a context of low antiapoptotic inputs, leading to mitotic catastrophe and apoptosis.…”

The AXL-PYK2-PKCα axis as a nexus of stemness circuits in TNBC

“…Cells were plated in 96-well plates and next day treated with TGFβ1 (10 ng/ml) for 24 h. The cells were then treated with the indicated concentrations of PYK2/FAK (PF396), FAK (PF228), or PKC (RO-31-8220) inhibitors, either alone or in combination in fresh media using DMSO as vehicle control. Inhibitor-treatment was continued for 72 h and cell viability was measured by MTT assay ( 60 ). Cell viability is shown as percentage of control.…”

Relevance of Membrane Contact Sites in Cancer Progression

“…Mechanistically, these therapies induce ferroptosis in correlation with the reduction of glutathione peroxidase 4, nuclear factor erythroid 2-related factor 2 (Nrf2), and glutathione metabolism. Therefore, drug combination might be a new therapeutic option for patients with triple-negative breast cancer, highlighting ferroptosis as a promising avenue for the treatment of TNBC ( Verma et al, 2020 ). Relevant to this issue is the finding that progesterone induces VDAC and sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) expression, inhibiting the growth of MCF-7 cells ( Azeez et al, 2018 ).…”