Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer

Qingjian Li, Tao Qin, Zhuofei Bi, Huangming Hong, Lin Ding, Jiewen Chen, Wei Wu, Xiaorong Lin, Wenkui Fu, Fang Zheng, Yandan Yao, Man-Li Luo, Phei Er Saw, Gerburg M. Wulf, Xiaoding Xu, Erwei Song, Herui Yao () and Hai Hu ()
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Qingjian Li: Sun Yat-Sen University
Tao Qin: Sun Yat-Sen University
Zhuofei Bi: Sun Yat-Sen University
Huangming Hong: Sun Yat-Sen University
Lin Ding: Sun Yat-Sen University
Jiewen Chen: Sun Yat-Sen University
Wei Wu: Sun Yat-Sen University
Xiaorong Lin: Sun Yat-Sen University
Wenkui Fu: Sun Yat-Sen University
Fang Zheng: Sun Yat-Sen University
Yandan Yao: Sun Yat-Sen University
Man-Li Luo: Sun Yat-Sen University
Phei Er Saw: Sun Yat-Sen University
Gerburg M. Wulf: Harvard Medical School
Xiaoding Xu: Sun Yat-Sen University
Erwei Song: Sun Yat-Sen University
Herui Yao: Sun Yat-Sen University
Hai Hu: Sun Yat-Sen University

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15308-7

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