Chemical-proteomics Identify Peroxiredoxin-1 as an Actionable Target in Triple-negative Breast Cancer

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to its aggressive nature and lack of targeted therapies.
• Identifying novel drugs that exploit specific oncogenic vulnerabilities in TNBC is crucial for improving patient outcomes.

Purpose of the Study:

• To evaluate the antitumor efficacy of CM728, a novel quinone-fused oxazepine, against triple-negative breast cancer.
• To elucidate the mechanism of action of CM728, including its molecular targets and downstream signaling pathways.
• To assess the potential of CM728 as a combination therapy with docetaxel for TNBC treatment.

Main Methods:

• In vitro cell viability assays and in vivo orthotopic tumor growth models were used to assess CM728's efficacy.
• Chemical proteomics and molecular docking were employed to identify CM728's molecular target.
• Western blotting and cell cycle analysis were performed to investigate CM728's effects on cellular signaling and apoptosis.

Main Results:

• CM728 demonstrated potent inhibition of TNBC cell viability and reduced tumor growth in vivo.
• CM728 exhibited synergistic antiproliferative effects when combined with docetaxel, outperforming individual treatments.
• CM728 was identified as a binder of peroxiredoxin-1 (Prdx1), inducing its oxidation and subsequent oxidative stress, JNK/p38 MAPK activation, and STAT3 inhibition.
• CM728 treatment led to DNA damage, cell cycle arrest, and caspase-dependent apoptosis.

Conclusions:

• CM728 is a novel compound with significant antitumoral activity against triple-negative breast cancer.
• The mechanism of action involves targeting Prdx1, inducing oxidative stress, and triggering apoptotic pathways.
• CM728 holds promise as a standalone therapy or in combination with other agents, like docetaxel, for TNBC treatment.