Therapeutic Targeting of Sunitinib-Induced AR Phosphorylation in Renal Cell Carcinoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-06, Vol.78 (11), p.2886-2896
• Main Authors: Adelaiye-Ogala, Remi, Damayanti, Nur P, Orillion, Ashley R, Arisa, Sreevani, Chintala, Sreenivasulu, Titus, Mark A, Kao, Chinghai, Pili, Roberto
• Format: Article
• Language: English
• Subjects: Androgen receptors; Androgens; Animals; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; Cell Line, Tumor; Drug resistance; Drug Resistance, Neoplasm - drug effects; Enzyme inhibitors; Female; Humans; Inhibitors; Kallikrein; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Kinases; Male; Mice; Mice, SCID; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; Phosphorylation; Phosphorylation - drug effects; Prostate cancer; Proteasomes; Protein arrays; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase receptors; Receptors, Androgen - metabolism; Renal cell carcinoma; Secretion; Serine; Signal Transduction - drug effects; Solid tumors; Sunitinib - pharmacology; Targeted cancer therapy; Therapeutic applications; Therapeutic targets; Tissue Kallikreins - metabolism; Transcription; Ubiquitin; Ubiquitin-protein ligase; Xenograft Model Antitumor Assays - methods; Xenografts
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-17-3386

Androgen receptor (AR) plays a crucial role in the development and progression of prostate cancer. AR expression has also been reported in other solid tumors, including renal cell carcinoma (RCC), but its biological role here remains unclear. Through integrative analysis of a reverse phase protein array, we discovered increased expression of AR in an RCC patient-derived xenograft model of acquired resistance to the receptor tyrosine kinase inhibitor (RTKi) sunitinib. AR expression was increased in RCC cell lines with either acquired or intrinsic sunitinib resistance An AR signaling gene array profiler indicated elevated levels of AR target genes in sunitinib-resistant cells. Sunitinib-induced AR transcriptional activity was associated with increased phosphorylation of serine 81 (pS81) on AR. Additionally, AR overexpression resulted in acquired sunitinib resistance and the AR antagonist enzalutamide-induced AR degradation and attenuated AR downstream activity in sunitinib-resistant cells, also indicated by decreased secretion of human kallikrein 2. Enzalutamide-induced AR degradation was rescued by either proteasome inhibition or by knockdown of the AR ubiquitin ligase speckle-type POZ protein (SPOP). treatment with enzalutamide and sunitinib demonstrated that this combination efficiently induced tumor regression in a RCC model following acquired sunitinib resistance. Overall, our results suggest the potential role of AR as a target for therapeutic interventions, in combination with RTKi, to overcome drug resistance in RCC. These findings highlight the therapeutic potential of targeting the androgen receptor to overcome RCC resistance to receptor tyrosine kinase inhibitors. .