Discovery of a transforming growth factor-β1 inhibitory peptide, Charis 1000 to enhance the therapeutic efficacy of paclitaxel in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive and invasive subtype of breast cancer for which chemotherapy, such as paclitaxel (PTX), remains a primary treatment option. However, resistance to chemotherapy poses a significant challenge, necessitating the development of novel therapeutic strategies. This study aimed to address PTX resistance in TNBC by developing a peptide drug, Charis 1000 (C1K), designed to target transforming growth factor beta (TGF-β) signaling. C1K was synthesized using standard solid-phase peptide synthesis and optimized for enhanced stability. Molecular docking predicted the binding interactions between C1K and TGF-β1, and surface plasmon resonance (SPR) confirmed a moderate binding affinity. The therapeutic potential of C1K was evaluated in TNBC cell lines (4T1, MDA-MB-231, and PTX-resistant MDA-MB-231) and in vivo using a syngeneic 4T1 mouse model. Functional assays demonstrated that C1K inhibited TGF-β-mediated signaling, reduced autophagy, a key mechanism underlying PTX resistance, and significantly enhanced PTX-induced apoptosis. In vivo studies further revealed synergistic effects of C1K and PTX, resulting in enhanced apoptosis in both sensitive and PTX-resistant TNBC cells. These findings suggest that C1K effectively targets TGF-β to inhibit autophagy and potentiate the apoptotic effects of PTX, as a promising combinatorial therapeutic agent for improving treatment outcomes in TNBC patients.