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Updated: Oct 27, 2025
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
ATM/NEMO signaling modulates the expression of PD-L1 following docetaxel chemotherapy in prostate cancer
Zongren Wang1,2, Xueling Zhang1, Wuguo Li3
1The Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Background:
The efficacy of docetaxel-based chemotherapy is limited by the development of drug resistance. Recent studies demonstrated the efficacy of anti-programmed death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immunotherapies in metastatic prostate cancer. The ataxia telangiectasia mutation (ATM) protein plays a crucial role in maintaining genome stability and function of mitosis. Here, we aimed to determine whether PD-1/PD-L1 signaling contributes to the resistance to DTX and to elucidate the mechanism underlying DTX-induced PD-L1 expression.
Methods:
In this retrospective study, PD-L1 expression was analyzed in 33 tumor tissue samples from prostate cancer patients. Prostate cell lines were used to perform functional assays and examine underlying mechanisms in vitro. A fully mouse prostate cancer model and a humanized chimeric mouse bearing human prostate tumors and peripheral blood mononuclear cells were used for in vivo assays.
Results:
We have shown that DTX, a chemotherapeutic drug which causing microtubule interference, could significantly induce the expression of PD-L1 in prostate cancer cells. This effect is blocked by the inhibition of ATM, suggesting that it plays an essential role in PD-L1 expression upregulated by DTX. Mechanistic studies have shown that ATM activity in cancer cells enhances the stability of the NF-κB essential modulator (NEMO), which leading to an increase in the NF-κB activity and PD-L1 expression. Using the mouse model, it was further demonstrated that a combination of ATM and NEMO inhibitors along with DTX augmented the antitumor efficacy of chemotherapy, which are comparable to that of PD-L1 antibody.
Conclusions:
Our findings have revealed that a previously unrecognized ATM-NEMO signaling which induced by DTX is capable of suppressing tumor immunity by activating the expression of PD-L1, suggesting that the ATM-NEMO-NF-κB axis can be exploited to restore the immune balance and overcome cancer resistance triggered by DTX.Graphic Abstract: supplementary file 1.
Insights
Docetaxel chemotherapy resistance in prostate cancer is linked to increased PD-L1 expression, driven by the ATM-NEMO-NF-κB pathway. Inhibiting this axis alongside docetaxel enhances anti-tumor immunity and efficacy.
Area of Science:
- Oncology
- Cancer Immunology
- Molecular Biology
Background:
- Docetaxel (DTX) chemotherapy efficacy in prostate cancer is limited by drug resistance.
- Anti-programmed death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immunotherapies show promise in metastatic prostate cancer.
- Ataxia telangiectasia mutation (ATM) protein is vital for genome stability and mitosis.
Purpose of the Study:
- To investigate if PD-1/PD-L1 signaling contributes to docetaxel resistance.
- To elucidate the mechanism behind docetaxel-induced PD-L1 expression.
Main Methods:
- Retrospective analysis of PD-L1 expression in 33 prostate cancer tumor samples.
- In vitro functional assays using prostate cancer cell lines.
- In vivo studies using mouse prostate cancer models and humanized chimeric mice.
Main Results:
- Docetaxel significantly increased PD-L1 expression in prostate cancer cells, an effect blocked by ATM inhibition.
- ATM activity enhances NEMO stability, increasing NF-κB activity and PD-L1 expression.
- Combination therapy with DTX, ATM, and NEMO inhibitors improved anti-tumor efficacy in mouse models.
Conclusions:
- DTX induces ATM-NEMO signaling, upregulating PD-L1 and suppressing anti-tumor immunity.
- The ATM-NEMO-NF-κB axis presents a therapeutic target to overcome DTX resistance and restore immune balance.
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