Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 510120, Guangzhou, People's Republic of China.
Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 510120, Guangzhou, People's Republic of China.
Nat Commun. 2020 Mar 19;11(1):1456. doi: 10.1038/s41467-020-15308-7.
Resistance development to one chemotherapeutic reagent leads frequently to acquired tolerance to other compounds, limiting the therapeutic options for cancer treatment. Herein, we find that overexpression of Rac1 is associated with multi-drug resistance to the neoadjuvant chemotherapy (NAC). Mechanistically, Rac1 activates aldolase A and ERK signaling which up-regulates glycolysis and especially the non-oxidative pentose phosphate pathway (PPP). This leads to increased nucleotides metabolism which protects breast cancer cells from chemotherapeutic-induced DNA damage. To translate this finding, we develop endosomal pH-responsive nanoparticles (NPs) which deliver Rac1-targeting siRNA together with cisplatin and effectively reverses NAC-chemoresistance in PDXs from NAC-resistant breast cancer patients. Altogether, our findings demonstrate that targeting Rac1 is a potential strategy to overcome acquired chemoresistance in breast cancer.
对一种化疗试剂的耐药性发展常常导致对其他化合物的获得性耐受，从而限制了癌症治疗的治疗选择。在这里，我们发现 Rac1 的过表达与新辅助化疗（NAC）的多药耐药性有关。在机制上，Rac1 激活醛缩酶 A 和 ERK 信号，上调糖酵解，特别是非氧化戊糖磷酸途径（PPP）。这导致核苷酸代谢增加，从而保护乳腺癌细胞免受化疗引起的 DNA 损伤。为了将这一发现转化为实际应用，我们开发了内体 pH 响应性纳米颗粒（NPs），这些 NPs 可以同时递送 Rac1 靶向 siRNA 和顺铂，并有效地逆转来自对 NAC 耐药的乳腺癌患者的 PDX 中的 NAC 化疗耐药性。总之，我们的研究结果表明，靶向 Rac1 是克服乳腺癌获得性耐药性的一种潜在策略。
