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Mcl-1 inhibition overcomes BET inhibitor resistance induced by low FBW7 expression in breast cancer
Xu Wang1, Xiaolin Wei1, Yu Cao1
1Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China.
Abstract:
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.
Insights
Low FBW7 expression causes breast cancer resistance to BET inhibitors like JQ1 by stabilizing Mcl-1. Combining BET inhibitors with Mcl-1 inhibitors may overcome this resistance in patients with low FBW7.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Bromodomains and extraterminal (BET) protein inhibitors (BETis) show therapeutic promise for breast cancer (BC).
- Drug resistance frequently limits the clinical efficacy of BETis in BC.
- The tumor suppressor FBW7's role in BC drug resistance is not well understood.
Purpose of the Study:
- To investigate the role of FBW7 in mediating resistance to BET inhibitors in breast cancer.
- To elucidate the molecular mechanisms underlying FBW7-associated drug resistance.
- To explore therapeutic strategies combining BET inhibitors with Mcl-1 inhibitors for BC.
Main Methods:
- shRNA-mediated FBW7 silencing in wild-type (WT) BC cells.
- Assessment of apoptosis induction upon JQ1 treatment.
- Western blot analysis to evaluate Mcl-1 protein levels.
- MCF7 xenograft mouse models to assess in vivo efficacy.
- Combination therapy studies with JQ1 and Mcl-1 inhibitor S63845.
Main Results:
- Low FBW7 expression correlated with resistance to JQ1 treatment in BC cells.
- FBW7 silencing led to Mcl-1 stabilization, abrogating JQ1-induced apoptosis.
- Mcl-1 knockdown or inhibition restored sensitivity to JQ1.
- FBW7 knockdown tumors exhibited JQ1 resistance in vivo.
- Combination of JQ1 and S63845 resensitized FBW7-deficient tumors to JQ1.
Conclusions:
- FBW7 deficiency contributes to BET inhibitor resistance in breast cancer via Mcl-1 stabilization.
- Targeting Mcl-1 in combination with BET inhibitors represents a potential therapeutic strategy for BC patients with low FBW7 expression.
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