Mapping Novel Metabolic Nodes Targeted by Anti-Cancer Drugs that Impair Triple-Negative Breast Cancer Pathogenicity

Triple-negative breast cancers (TNBCs)
are estrogen receptor, progesterone receptor, and HER2 receptor-negative
subtypes of breast cancers that show the worst prognoses and lack
targeted therapies. Here, we have coupled the screening of ∼400
anticancer agents that are under development or in the clinic with
chemoproteomic and metabolomic profiling to identify novel metabolic
mechanisms for agents that impair TNBC pathogenicity. We identify
20 anticancer compounds that significantly impaired cell survival
across multiple types of TNBC cells. Among these 20 leads, the phytoestrogenic
natural product licochalcone A was of interest, since TNBCs are unresponsive
to estrogenic therapies, indicating that licochalcone A was likely
acting through another target. Using chemoproteomic profiling approaches,
we reveal that licochalcone A impairs TNBC pathogenicity, not through
modulating estrogen receptor activity but rather through inhibiting
prostaglandin reductase 1, a metabolic enzyme involved in leukotriene
B4 inactivation. We also more broadly performed metabolomic profiling
to map additional metabolic mechanisms of compounds that impair TNBC
pathogenicity. Overlaying lipidomic profiling with drug responses,
we find that deubiquitinase inhibitors cause dramatic elevations in
acyl carnitine levels, which impair mitochondrial respiration and
contribute to TNBC pathogenic impairments. We thus put forth two unique
metabolic nodes that are targeted by drugs or drug candidates that
impair TNBC pathogenicity. Our results also showcase the utility of
coupling drug screens with chemoproteomic and metabolomic profiling
to uncover unique metabolic drivers of TNBC pathogenicity.