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Cytotoxic chemotherapy is initially effective in patients with metastatic triple-negative breast cancer (mTNBC). However, most of the TNBC patients have high risk of recurrence after chemotherapy and metastatic tumor recurrence indicates rapid tumor proliferation and drug resistance. In TNBC cells, treatment with the chemotherapeutic drug paclitaxel (PTX) induces Transforming growth factor (TGF)-β signaling pathway. TGF-β is a master regulator of tumor angiogenesis and epithelial-mesenchymal transition (EMT), which are limiting the efficacy of cancer therapies and suppressing the anti-tumor immune response. TGF-β induces autophagy in tumor cells and autophagy is closely associated with cancer cell survival and contributing to resistance to therapies. The targeting of TGF-β pathway is possibly an effective strategy to inhibit drug resistance and increase the sensitivity of cancer treatment. Charis 1000 (C1K), which is currently under development, is a synthetic peptide that targets TGF-β1. As C1K partially inhibits TGF-β1-induced Smad2 phosphorylation in TNBC cells, there is no risk of side effects unlike small molecules or antibodies that completely inhibit the TGF-β1 signaling pathway. Combination therapies including chemotherapy are actively investigated as effective treatments for various cancers. PTX, one of frequently used drugs in combination therapies, increases phosphorylation of Smad2, a TGF- β1 downstream signaling pathway and induces autophagy in TNBC cells, but PTX in combination with C1K increases apoptosis while reducing Smad2 phosphorylation and autophagy. The combination of C1K with PTX in the mouse TNBC model showed significant tumor size reduction in comparison to the PTX alone group. In addition, the combination of C1K with PTX confirmed the increased apoptosis and decreased autophagy in the tumor tissues. Furthermore, the combination of C1K with PTX increased the survival rate of mice that was reduced due to the side effects of PTX. These data indicate that the drug resistance induced by TGF-β signaling pathway can be suppressed by C1K combination through TGF-β signaling modulation. C1K may be a promising combination partner for cancer treatment by reducing drug resistance and increasing apoptotic potential of anticancer drugs. Currently, a phase1 clinical trial of the C1K combination therapy with PTX is ongoing and the preclinical studies of the C1K combination with immune checkpoint inhibitors (ICIs) are actively investigated as well. Citation Format: Youl-Nam Lee, Yun-hee Han, Won-Sam Kim, Cheol-Min Lee, Eun-Joung Moon, Hae-Jin Kim. A promising combination partner for paclitaxel in triple-negative breast cancer (TNBC) therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5304. |
