Ansari Shamima Azma, Mohanty Sibasish, Mohapatra Pallavi, Datta Sudeshna, Swain Mamuni, Rath Rachna, Muduly Dillip K, Majumdar Saroj K D, Swain Rajeeb K, Raghav Sunil K, Dash Rupesh
Institute of Life Sciences, Bhubaneswar, Odisha, India.
Regional Centre for Biotechnology, Faridabad, India.
Br J Cancer. 2025 Sep 9. doi: 10.1038/s41416-025-03148-5.
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.
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.
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.
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.
多西他赛是包括晚期口腔鳞状细胞癌（OSCC）在内的多种肿瘤最常用的化疗方案。不幸的是，化疗耐药会导致复发和不良的疾病结局。
我们进行了基于CRISPR的激酶组筛选，以确定多西他赛耐药的潜在相关因素。进行免疫组织化学检测以检查肿瘤组织中靶基因的表达谱。进行全转录组分析以确定多西他赛耐药的分子机制。进行NEK9激酶测定以鉴定一种推定的激酶抑制剂。
在基于CRISPR的激酶组筛选中，有丝分裂基因A相关激酶9（NEK9）被确定为OSCC、前列腺癌和胰腺癌系中多西他赛耐药的主要相关因素。与有反应者相比，在化疗无反应的OSCC患者中发现NEK9表达上调。NEK9基因敲除可恢复多西他赛诱导的化疗耐药细胞的细胞死亡。从机制上讲，我们发现NEK9缺失会上调转导素样增强蛋白3（TLE3），进而抑制Wnt信号通路。福斯替尼被鉴定为一种有效的NEK9抑制剂，可克服多西他赛耐药。
我们的研究表明，NEK9在多西他赛耐药中起重要作用。NEK9抑制剂福斯替尼与多西他赛的新组合在晚期OSCC中需要进一步的临床研究。
