Therapeutic Targeting of Nemo-like Kinase in Primary and Acquired Endocrine-resistant Breast Cancer
| Autor: | Xixi Cao, Jamunarani Veeraraghavan, Shunqiang Li, Martin Shea, Lanfang Qin, Ying Tan, Susan G. Hilsenbeck, Xian Wang, Xiaosong Wang, Yiheng Hu, Jin-Ah Kim, Ling Lin, Tamika Mitchell, Rachel Schiff, Chia Chia Liu, Suet Kee Loo, Matthew J. Ellis, Sanghoon Lee |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Antineoplastic Agents Hormonal Cell Survival p38 mitogen-activated protein kinases Estrogen receptor Breast Neoplasms Protein Serine-Threonine Kinases Article Mice 03 medical and health sciences 0302 clinical medicine Breast cancer Cell Line Tumor Coactivator Biomarkers Tumor medicine Animals Humans Phosphorylation Protein Kinase Inhibitors Everolimus Dose-Response Relationship Drug Kinase business.industry Gene Expression Profiling Estrogen Receptor alpha Prognosis medicine.disease Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic Disease Models Animal 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Female business Tamoxifen Signal Transduction medicine.drug |
| Zdroj: | Clin Cancer Res |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Endocrine resistance remains a major clinical challenge in estrogen receptor (ER)–positive breast cancer. Despite the encouraging results from clinical trials for the drugs targeting known survival signaling, relapse is still inevitable. There is an unmet need to discover new drug targets in the unknown escape pathways. Here, we report Nemo-like kinase (NLK) as a new actionable kinase target that endows previously uncharacterized survival signaling in endocrine-resistant breast cancer. Experimental Design: The effects of NLK inhibition on the viability of endocrine-resistant breast cancer cell lines were examined by MTS assay. The effect of VX-702 on NLK activity was verified by kinase assay. The modulation of ER and its coactivator, SRC-3, by NLK was examined by immunoprecipitation, kinase assay, luciferase assay, and RNA sequencing. The therapeutic effects of VX-702 and everolimus were tested on cell line- and patient-derived xenograft (PDX) tumor models. Results: NLK overexpression endows reduced endocrine responsiveness and is associated with worse outcome of patients treated with tamoxifen. Mechanistically, NLK may function, at least in part, via enhancing the phosphorylation of ERα and its key coactivator, SRC-3, to modulate ERα transcriptional activity. Through interrogation of a kinase profiling database, we uncovered and verified a highly selective dual p38/NLK inhibitor, VX-702. Coadministration of VX-702 with the mTOR inhibitor, everolimus, demonstrated a significant therapeutic effect in cell line-derived xenograft and PDX tumor models of acquired or de novo endocrine resistance. Conclusions: Together, this study reveals the potential of therapeutic modulation of NLK for the management of the endocrine-resistant breast cancers with active NLK signaling. |
| Databáze: | OpenAIRE |
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