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Updated: Jan 18, 2026
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
NEK9-mediated Wnt signalling repressor TLE3 rewires Docetaxel resistance in cancer cells by inducing pyroptosis
Shamima Azma Ansari1,2, Sibasish Mohanty1,2, Pallavi Mohapatra1,2
1Institute of Life Sciences, Bhubaneswar, Odisha, India.
Background:
Docetaxel is the most common chemotherapy regimen for several neoplasms, including advanced OSCC (Oral Squamous Cell Carcinoma). Unfortunately, chemoresistance leads to relapse and adverse disease outcomes.
Methods:
We performed CRISPR-based kinome screening to identify potential players of Docetaxel resistance. Immunohistochemistry was performed to examine the expression profile of the target gene across tumour tissues. Global transcriptome analysis was performed to determine the molecular mechanism underlying Docetaxel resistance. NEK9 kinase assay was performed to identify a putative kinase inhibitor.
Results:
Upon conducting CRISPR-based kinome screening, Never In Mitosis Gene-A Related Kinase-9 (NEK9) was identified as a major player of Docetaxel resistance in OSCC, prostate, and pancreatic cancer lines. NEK9 expression was found to be upregulated in chemotherapy non-responder OSCC patients as compared to responders. NEK9 ablation restores Docetaxel-induced cell death in chemoresistant cells. Mechanistically, we found that NEK9 deletion upregulates Transducin-like enhancer protein 3 (TLE3), which in turn represses Wnt signalling. Fostamatinib was identified as a potent NEK9 inhibitor that overcomes Docetaxel resistance.
Conclusions:
Our study demonstrated that NEK9 plays an important role in Docetaxel resistance. The novel combination of NEK9 inhibitor Fostamatinib and Docetaxel needs further clinical investigation in advanced OSCC.
Insights
Never In Mitosis Gene-A Related Kinase-9 (NEK9) drives Docetaxel resistance in oral cancer by repressing Wnt signaling. Inhibiting NEK9 with Fostamatinib may restore chemotherapy effectiveness in OSCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Docetaxel is a primary chemotherapy for oral squamous cell carcinoma (OSCC).
- Chemotherapy resistance is a significant challenge, leading to cancer relapse and poor outcomes.
- Identifying mechanisms of resistance is crucial for improving treatment efficacy.
Purpose of the Study:
- To identify key molecular players involved in Docetaxel resistance in OSCC using CRISPR-based kinome screening.
- To elucidate the underlying molecular mechanisms of Docetaxel resistance mediated by NEK9.
- To identify potential therapeutic strategies to overcome Docetaxel resistance.
Main Methods:
- CRISPR-based kinome screening to identify resistance-associated kinases.
- Immunohistochemistry to analyze target gene expression in patient tumor tissues.
- Global transcriptome analysis to understand molecular pathways.
- NEK9 kinase assays to identify inhibitors.
Main Results:
- Never In Mitosis Gene-A Related Kinase-9 (NEK9) was identified as a critical factor in Docetaxel resistance across multiple cancer types (OSCC, prostate, pancreatic).
- NEK9 expression is elevated in OSCC patients resistant to chemotherapy compared to responders.
- NEK9 depletion restores sensitivity to Docetaxel by upregulating TLE3, which subsequently represses Wnt signaling.
- Fostamatinib was identified as a potent NEK9 inhibitor capable of overcoming Docetaxel resistance.
Conclusions:
- NEK9 plays a significant role in mediating Docetaxel resistance in cancer, particularly in OSCC.
- Targeting NEK9 with inhibitors like Fostamatinib presents a promising strategy to enhance Docetaxel efficacy.
- The combination of NEK9 inhibition and Docetaxel warrants further clinical investigation for advanced OSCC treatment.
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