Open AccessMcl‐1 inhibition overcomes BET inhibitor resistance induced by low FBW7 expression in breast cancer
Author(s) -
Wang Xu,
Wei Xiaolin,
Cao Yu,
Xing Peng
Publication year - 2022
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.17210
Subject(s) - gene knockdown , gene silencing , downregulation and upregulation , cancer research , apoptosis , bromodomain , small hairpin rna , in vivo , biology , epigenetics , gene , biochemistry , genetics
While the promise of bromodomains and extraterminal (BET) protein inhibitors (BETis) is emerging in breast cancer (BC) therapy, resistance in these cells to BETis conspicuously curbs their therapeutic potential. FBW7 is an important tumour suppressor. However, the role of FBW7 in BC is not clear. In the current study, our data indicated that the low expression of FBW7 contributes to the drug resistance of BC cells upon JQ1 treatment. shRNA‐mediated FBW7 silencing in FBW7 WT BC cells suppressed JQ1‐induced apoptosis. Mechanistically, it was revealed that this diminished FBW7 level leads to Mcl‐1 stabilization, while Mcl‐1 upregulation abrogates the killing effect of JQ1. Mcl‐1 knockdown or inhibition resensitized the BC cells to JQ1‐induced apoptosis. Moreover, FBW7 knockdown in MCF7 xenografted tumours demonstrated resistance to JQ1 treatment. The combination of JQ1 with a Mcl‐1 inhibitor (S63845) resensitized the FBW7 knockdown tumours to JQ1 treatment in vivo . Our study paves the way for a novel therapeutic potential of BETis with Mcl‐1 inhibitors for BC patients with a low FBW7 expression.