School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, Brisbane, QLD 4102, Australia.
Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia.
Pharmacol Res. 2024 Sep;207:107298. doi: 10.1016/j.phrs.2024.107298. Epub 2024 Jul 18.
Acquired drug resistance is the major cause for disease recurrence in cancer patients, and this is particularly true for patients with metastatic melanoma that carry a BRAF mutation. To address this problem, we investigated cyclic membrane-active peptides as an alternative therapeutic modality to kill drug-tolerant and resistant melanoma cells to avoid acquired drug resistance. We selected two stable cyclic peptides (cTI and cGm), previously shown to have anti-melanoma properties, and compared them with dabrafenib, a drug used to treat cancer patients with the BRAF mutation. The peptides act via a fast membrane-permeabilizing mechanism and kill metastatic melanoma cells that are sensitive, tolerant, or resistant to dabrafenib. Melanoma cells do not become resistant to long-term treatment with cTI, nor do they evolve their lipid membrane composition, as measured by lipidomic and proteomic studies. In vivo studies in mice demonstrated that the combination treatment of cTI and dabrafenib resulted in fewer metastases and improved overall survival. Such cyclic membrane-active peptides are thus well suited as templates to design new anticancer therapeutic strategies.
获得性耐药是癌症患者疾病复发的主要原因，这对于携带 BRAF 突变的转移性黑色素瘤患者尤其如此。为了解决这个问题，我们研究了环状膜活性肽作为一种替代治疗方法，以杀死耐受和耐药的黑色素瘤细胞，从而避免获得性耐药。我们选择了两种稳定的环状肽（cTI 和 cGm），它们先前被证明具有抗黑色素瘤特性，并将它们与 dabrafenib 进行了比较，dabrafenib 是一种用于治疗携带 BRAF 突变的癌症患者的药物。这些肽通过快速的膜渗透机制起作用，并杀死对 dabrafenib 敏感、耐受或耐药的转移性黑色素瘤细胞。黑色素瘤细胞不会对 cTI 的长期治疗产生耐药性，也不会像脂质组学和蛋白质组学研究所测量的那样改变其脂质膜组成。在小鼠体内研究中，cTI 和 dabrafenib 的联合治疗导致转移减少，总生存率提高。因此，这种环状膜活性肽非常适合作为设计新的抗癌治疗策略的模板。
