Targeting Bcl-xL to eliminate chemotherapy-induced tumor dormancy and prevent breast cancer metastasis

TL;DR

This study shows that targeting Bcl-xL can help eliminate chemotherapy-induced dormant cancer cells and prevent breast cancer from spreading.

Contribution

The study identifies Bcl-xL as a key survival factor in dormant cancer cells and proposes targeted therapy with A-1331852 to prevent metastasis.

Findings

Dormant cancer cells across multiple models consistently showed high Bcl-xL expression.

Pharmacologic inhibition of Bcl-xL with A-1331852 improved chemotherapy outcomes and reduced relapse.

Intratumoral delivery of A-1331852 was effective but failed to eliminate early lung dissemination.

Abstract

Chemotherapy-induced tumor dormancy is a major barrier to curative cancer therapy, particularly in triple-negative breast cancer (TNBC), where dormant residual cells evade treatment and fuel late relapses. To define survival mechanisms sustaining dormancy, we examined four breast cancer models: HER2-positive murine MMC and human SK-BR-3, and TNBC murine 4T1 and human MDA-MB-231. Dormancy was induced with low-dose FAC (5-Fluorouracil, Adriamycin, Cyclophosphamide). Across all models, dormant cells maintained high Bcl-xL expression. shRNA knockdown of Bcl-xL increased chemotherapy-induced apoptosis and prevented relapse in vitro and in vivo. Pharmacologic inhibition with A-1331852 improved chemotherapy, particularly in TNBC, and transient dosing avoided compensatory Survivin induction. Systemic A-1331852 suppressed relapse but caused off-target toxicity, whereas intratumoral delivery preserved efficacy and safety but failed to eliminate early lung dissemination, as confirmed by ex vivo culture of dormant tumor cells. Notably, disseminated cell frequency inversely correlated with primary tumor size during neoadjuvant chemotherapy, underscoring the need for systemic therapies targeting distant dormant cells. These findings identify Bcl-xL as a central survival factor in chemotherapy-induced dormancy, and suggest that tumor-targeted systemic delivery of A-1331852 may eradicate disseminated dormant cells and prevent metastatic relapse in high-risk TNBC.

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