Androgen deprivation therapy (ADT) with or without antiandrogens such as enzalutamide is the mainstay of treatment in advanced prostate cancer (PC). However, new therapeutic strategies are needed for patients who relapse on antiandrogen therapy. The glucocorticoid receptor (GR) has been implicated as a potential antiandrogen bypass mechanism. We previously showed that ORIC-101, a potent and selective, orally bioavailable small molecule GR antagonist, reverses GR-mediated resistance to enzalutamide in preclinical PC models. In the clinic, we are evaluating ORIC-101 in combination with enzalutamide in patients with metastatic prostate cancer (NCT04033328). Activation of the PI3K/AKT pathway through PTEN loss is a poor prognostic factor and another potential resistance mechanism to anti-hormone directed therapies. Reciprocal crosstalk between androgen signaling and PI3K/AKT pathway activation forms the basis for the clinical development of AKT inhibitors (AKTi) in combination with ADT or antiandrogens (NCT03072238, NCT04087174). In this study, we tested preclinically whether activated GR confers resistance to the combination of AKT inhibitors with enzalutamide and whether co-treatment with ORIC-101 reverses GR-mediated resistance to an enzalutamide/AKTi doublet.
We first evaluated the effects of enzalutamide plus AKTi treatment on GR levels, GR target genes and activity in three prostate cancer cell lines: PTEN-null line LNCaP and PTEN-wildtype lines VCaP and CWR22PC. We tested three AKT inhibitors: the ATP-competitive inhibitors ipatasertib (GDC-0068) and capivasertib (AZD5363), in addition to the allosteric inhibitor MK2206, in CSS media and 10% FBS, with or without supplementation of the synthetic glucocorticoid, dexamethasone. An increase in the protein and mRNA levels of GR and GR target genes was observed after 7 days of enzalutamide treatment. In the AKTi plus enzalutamide setting, AKT inhibition did not block the enzalutamide-mediated GR upregulation in either PTEN-null or PTEN-wildtype cells.
We next evaluated whether increased GR activity mediates resistance to the enzalutamide/AKTi doublet with ipatasertib or capivasertib, and whether this resistance can be reversed with ORIC-101. GR activation with dexamethasone promoted tumor cell growth and androgen-regulated gene expression in the presence of enzalutamide and ipatasertib or capivasertib, using a 21-day proliferation assay in CWR22PC cells. ORIC-101 was able to reverse these dexamethasone-induced effects, confirmed by reduced secreted PSA levels and cell number measured at end of study. These findings indicate that GR upregulation and activation, an established resistance mechanism for antiandrogens, may drive resistance when combined with an AKT inhibitor, and the GR antagonist ORIC-101 is able to overcome this resistance and restore antitumor activity.
Citation Format: Shravani Barkund, Haiying Zhou, Lori S. Friedman, Anneleen Daemen. GR antagonist ORIC-101 overcomes GR-mediated resistance to the combination of AR and AKT inhibition in preclinical prostate cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1420.