OTSSP167 suppresses TNBC brain metastasis via ROS-driven P38/JNK and FAK/ERK pathways

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Triple-negative breast cancer (TNBC) brain metastasis (BM) presents a significant therapeutic challenge.
• Effective treatments targeting TNBC BM, especially those crossing the blood-brain barrier (BBB), are urgently needed.

Purpose of the Study:

• To investigate the anti-cancer effects and underlying mechanisms of OTSSP167, a selective MELK inhibitor, against TNBC brain metastasis.
• To evaluate OTSSP167's efficacy and safety in preclinical models of TNBC BM.

Main Methods:

• In vitro studies assessed TNBC cell proliferation, migration, invasion, apoptosis, and cell cycle.
• Mechanistic studies explored reactive oxygen species (ROS) generation and downstream signaling pathways (P38/JNK, FAK/ERK).
• In vivo studies utilized murine xenograft and brain-tropic metastasis models to evaluate OTSSP167's efficacy and toxicity.

Main Results:

• OTSSP167 significantly suppressed TNBC cell proliferation, migration, and invasion, while inducing apoptosis and G1 cell cycle arrest.
• OTSSP167 triggered mitochondrial ROS overproduction, activating stress-response pathways and inhibiting pro-metastatic signaling.
• ROS scavenging reversed OTSSP167's anti-tumor effects, confirming ROS as a key mediator.
• OTSSP167 demonstrated efficacy in inhibiting primary tumor growth and BM in vivo without significant hepatorenal toxicity.
• The drug effectively crossed the BBB and exerted anti-tumor activity in a brain metastasis model.

Conclusions:

• OTSSP167 exhibits potent anti-metastatic activity against TNBC BM through a redox-dependent mechanism involving ROS.
• Its ability to cross the BBB and favorable safety profile position OTSSP167 as a promising therapeutic candidate for TNBC BM.
• Targeting MELK and ROS-dependent pathways represents a viable strategy for addressing unmet clinical needs in TNBC management.