TY - JOUR
T1 - Therapeutic targeting of nemo-like kinase in primary and acquired endocrine-resistant breast cancer
AU - Wang, Xian
AU - Veeraraghavan, Jamunarani
AU - Liu, Chia Chia
AU - Cao, Xixi
AU - Qin, Lanfang
AU - Kim, Jin Ah
AU - Tan, Ying
AU - Loo, Suet Kee
AU - Hu, Yiheng
AU - Lin, Ling
AU - Lee, Sanghoon
AU - Shea, Martin J.
AU - Mitchell, Tamika
AU - Li, Shunqiang
AU - Ellis, Matthew J.
AU - Hilsenbeck, Susan G.
AU - Schiff, Rachel
AU - Wang, Xiao Song
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - 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 RNAsequencing. The therapeutic effects of VX-702 and everolimus were tested on cell line- and patientderived 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 ERa and its key coactivator, SRC-3, to modulate ERa 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 endocrineresistant breast cancers with active NLK signaling.
AB - 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 RNAsequencing. The therapeutic effects of VX-702 and everolimus were tested on cell line- and patientderived 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 ERa and its key coactivator, SRC-3, to modulate ERa 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 endocrineresistant breast cancers with active NLK signaling.
UR - http://www.scopus.com/inward/record.url?scp=85105289374&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-2961
DO - 10.1158/1078-0432.CCR-20-2961
M3 - Article
C2 - 33542078
AN - SCOPUS:85105289374
SN - 1078-0432
VL - 27
SP - 2648
EP - 2662
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -