Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-020-15308-7
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Funding
- National Science and Technology Major Project [2020ZX09201021]
- Natural Science Foundation of China [81672738, 81730077, 81572596, U1601223, 81972471]
- National Key Research and Development Program of China [2016YFC1302301]
- Sun Yat-Sen University Clinical Research 5010 Program [2018007]
- Sun Yat-Sen Clinical Research Cultivating Program [SYS-C-201801]
- Program from Guangdong Introducing Innovative and Entrepreneurial Teams [2016ZT06S252]
- Natural Science Foundation of Guangdong Province [2017A030313828]
- Guangzhou Science and Technology Bureau [201704020095]
- Fundamental Research Funds for the Central Universities [17ykjc14]
- Guangdong Science and Technology Department [2017B030314026]
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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. Acquired resistance to chemotherapy can lead to multi-drug resistance and poor prognosis in cancer. Here, the authors show that Rac1 increases glycolysis and non-oxidative pentose phosphate pathway activity leading to neoadjuvant chemotherapy (NAC) resistance, thus its inhibition sensitizes resistant breast cancer PDXs to NAC.
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