Therapeutic targeting of sunitinib-induced AR phosphorylation in renal cell carcinoma

Remi Adelaiye-Ogala, Nur P. Damayanti, Ashley R. Orillion, Sreevani Arisa, Sreenivasulu Chintala, Mark A. Titus, Chinghai Kao, Roberto Pili

Research output: Contribution to journalArticle

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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 in vitro. 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). In vivo 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. Significance: These findings highlight the therapeutic potential of targeting the androgen receptor to overcome RCC resistance to receptor tyrosine kinase inhibitors.

Original languageEnglish (US)
Pages (from-to)2886-2896
Number of pages11
JournalCancer Research
Volume78
Issue number11
DOIs
StatePublished - Jun 1 2018

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Androgen Receptors
Renal Cell Carcinoma
Phosphorylation
Therapeutics
Receptor Protein-Tyrosine Kinases
sunitinib
Androgen Receptor Antagonists
Tissue Kallikreins
Protein Array Analysis
Proteasome Endopeptidase Complex
Ligases
Ubiquitin
Drug Resistance
Heterografts
Serine
Genes
Neoplasms
Prostatic Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Adelaiye-Ogala, R., Damayanti, N. P., Orillion, A. R., Arisa, S., Chintala, S., Titus, M. A., ... Pili, R. (2018). Therapeutic targeting of sunitinib-induced AR phosphorylation in renal cell carcinoma. Cancer Research, 78(11), 2886-2896. https://doi.org/10.1158/0008-5472.CAN-17-3386

Therapeutic targeting of sunitinib-induced AR phosphorylation in renal cell carcinoma. / Adelaiye-Ogala, Remi; Damayanti, Nur P.; Orillion, Ashley R.; Arisa, Sreevani; Chintala, Sreenivasulu; Titus, Mark A.; Kao, Chinghai; Pili, Roberto.

In: Cancer Research, Vol. 78, No. 11, 01.06.2018, p. 2886-2896.

Research output: Contribution to journalArticle

Adelaiye-Ogala, R, Damayanti, NP, Orillion, AR, Arisa, S, Chintala, S, Titus, MA, Kao, C & Pili, R 2018, 'Therapeutic targeting of sunitinib-induced AR phosphorylation in renal cell carcinoma', Cancer Research, vol. 78, no. 11, pp. 2886-2896. https://doi.org/10.1158/0008-5472.CAN-17-3386
Adelaiye-Ogala R, Damayanti NP, Orillion AR, Arisa S, Chintala S, Titus MA et al. Therapeutic targeting of sunitinib-induced AR phosphorylation in renal cell carcinoma. Cancer Research. 2018 Jun 1;78(11):2886-2896. https://doi.org/10.1158/0008-5472.CAN-17-3386
Adelaiye-Ogala, Remi ; Damayanti, Nur P. ; Orillion, Ashley R. ; Arisa, Sreevani ; Chintala, Sreenivasulu ; Titus, Mark A. ; Kao, Chinghai ; Pili, Roberto. / Therapeutic targeting of sunitinib-induced AR phosphorylation in renal cell carcinoma. In: Cancer Research. 2018 ; Vol. 78, No. 11. pp. 2886-2896.
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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 in vitro. 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). In vivo 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. Significance: These findings highlight the therapeutic potential of targeting the androgen receptor to overcome RCC resistance to receptor tyrosine kinase inhibitors.",
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