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 were examined by immunoprecipitation, kinase assay, luciferase assay, and RNAseq. The therapeutic effects of VX-702 and Everolimus were tested on cell line- and patient-derived xenograft tumor models. Resul ts: NLK overexpression endow reduced endocrine responsiveness and is associated with worse outcome of tamoxifen-treated patients. Mechanistically, NLK may function at last 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. Co-administration of VX-702 with the mTOR inhibitor Everolimus demonstrated a significant therapeutic effect in cell line- and patient-derived xenograft 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.
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου