Targeting c-Myc enhances immunotherapy efficacy in combination with Ras inhibitor in triple-negative breast cancer

Abstract

Background: Triple-negative breast cancer (TNBC), which lacks hormone receptors and HER2 expression, presents substantial therapeutic challenges in breast cancer treatment. The efficacy of immunotherapy frequently suffers from the immunosuppressive nature of tumour microenvironment (TME). Hence, discovering effective targets to hinder TNBC progression and bolster immunotherapy's effectiveness is paramount. Previous research from our team indicated notable upregulation of c-Myc in TNBC, and suppressing c-Myc enhances the efficacy of PD-L1 blockade in murine models; nevertheless, the precise mechanisms underlying this phenomenon remain elusive.

Methods: We analysed c-Myc expression and implemented a systematic drug library screening strategy alongside c-Myc knockdown to pinpoint potential synergistic agents in TNBC cells. To decipher the regulatory mechanisms of this synergy on cellular malignancy, we conducted cell cycle analysis, cell interaction assays, and RNA-sequencing. Additionally, we established orthotopic and lung metastasis murine models assess how combination therapy influences PD-L1 blockade efficacy.

Results: Elevated c-Myc was observed in TNBC and the Ras inhibitor Salirasib was identified as a potent synergistic agent from cell cycle drug library in c-Myc-overexpressing TNBC. The application of Salirasib combined with c-Myc knockdown markedly suppressed tumour cell aggressiveness and induced apoptosis in vitro. Mechanistically, RNA sequencing revealed that the combination therapy blocked MCM2-mediated DNA replication in TNBC cells, causing G1/S phase arrest and enhancing tumour suppression. In vivo, the combination significantly improved PD-L1 blockade efficacy, leading to reduction of tumour volume, inhibition of lung metastases, and remodelling of the immune microenvironment in murine TNBC models.

Conclusions: In summary, our investigation identifies a molecular vulnerability in c-Myc-driven TNBC, where Ras inhibition reinforces c-Myc-targeted therapy and potentiates immune checkpoint blockade, presenting a promising strategy to improve immunotherapy efficacy in TNBC.

Keywords

c-Myc / immunotherapy / Minichromosome Maintenance Complex Component 2 (MCM2) / Salirasib / triple-negative breast cancer (TNBC) / tumour microenvironment (TME)

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.