Targeting SIK2 with GRN-300 Potentiates Paclitaxel Efficacy in Triple-Negative Breast Cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Triple-Negative Breast Cancer (TNBC) lacks targeted therapies, relying on chemotherapy like paclitaxel.
• TNBC frequently develops chemoresistance, creating a need for novel treatment strategies.
• Salt-inducible kinase 2 (SIK2) is overexpressed in most TNBC cases.

Purpose of the Study:

• To develop and evaluate GRN-300, a novel SIK2 inhibitor, for its potential to sensitize TNBC to paclitaxel.
• To assess the efficacy of GRN-300 in combination with paclitaxel in vitro and in vivo.

Main Methods:

• Developed ARN-3261/GRN-300, an orally bioavailable SIK2 inhibitor.
• Tested GRN-300 and paclitaxel combination in eight TNBC cell lines and xenograft models.
• Investigated the mechanistic effects of GRN-300 on mitotic regulatory pathways.

Main Results:

• GRN-300 showed strong synergy with paclitaxel in all tested TNBC cell lines.
• Combination therapy significantly inhibited tumor growth and prolonged survival in vivo.
• GRN-300 disrupted the APC/C pathway, enhancing cell cycle arrest and apoptosis.

Conclusions:

• GRN-300 enhances paclitaxel efficacy by complementary disruption of mitotic pathways.
• GRN-300 demonstrates potential as a therapeutic agent for TNBC.
• These findings provide a strong preclinical rationale for the clinical development of GRN-300 in TNBC.