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

Abstract

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. .

Androgen Receptor promotes renal cell carcinoma (RCC) vasculogenic mimicry (VM)viaaltering TWIST1 nonsense-mediated decay through lncRNA-TANAR

“…This is consistent with the higher incidence and more malignant phenotypes in males according to data from the Surveillance Epidemiology and End Results (SEER) database (5)(6)(7). Furthermore, targeting AR with the antiandrogen enzalutamide could restore sunitinib sensitivity in the sunitinib-resistant PDX mouse model, suggesting enhancing TKI efficacy through inhibition of AR to better suppress ccRCC progression (8). Paradoxically, a higher expression of AR is associated with better prognosis based on a retrospective analysis from the TCGA database, indicating that AR function in ccRCC is complex and may be tumor stage-dependent (9).…”

Targeting the TR4 nuclear receptor-mediated lncTASR/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression

“…To approximate in vitro tissue culture cells to in vivo condition after sunitinib treatment, which results in a hypoxic tumor microenvironment, we attempted a comparison of the molecular changes of RCC cells under hypoxia versus normoxia conditions with a focus on TR4 protein. This is an extension of the recent study of another nuclear hormone receptor, androgen receptor, in its association with the acquired sunitinib resistance [32]. These studies indicate that nuclear hormone receptors can play a significant role in RCC resistance to sunitinib, raising the possibility of using small molecule hormones as adjuvant therapies for sunitinib.…”

Targeting the PI3K/AKT pathway overcomes enzalutamide resistance by inhibiting induction of the glucocorticoid receptor

“…Cell lines and xenograft tumors collected at the end of treatment (EOT) time point were lysed using standard protocol. Lysates generated were used to perform immunoblot as previously described 19 . Primary antibodies are diluted 1:1000 and from Santa Cruz (AR) or Cell Signaling Technology (AKT, p-AKT(Thr308), p-AKT (Ser483), GR, P70S6K, p-P70S6K, 4EBP1, p-4EBP1, and GAPDH).…”

“…mRNA extracts from cell lines and xenograft collected post EOT time points were used to perform qRT-PCR as previously described 19 for detection of KLK3, NKX3-1, and NR3C1 (Supplemental Table 1). PCR was performed on a StepOnePlus Real-Time PCR System (Applied Biosystems).…”