Abstract 5211: Therapeutic resistance to anti-AR signal pathway therapies is related to compensatory pathway activation and immune suppression in mouse Pten/Trp53-deficient CRPC
Authors: De Velasco Marco A. , Kura Yurie , Ando Naomi , Sako Noriko , Sakai Kazuko , Fujita Kazutoshi , Banno Eri , Nozawa Masahiro , Yoshimura Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: June 2022

Prostate cancers depend on androgens and the androgen receptor (AR) to drive androgen signaling pathways. Androgen-deprivation therapy (ADT) and second-generation antiandrogens have become the new standard of care for men with prostate cancer. However, resistance to these therapies remains a problem. TP53 mutations and PTEN loss have been associated with patients who fail to respond to anti-androgen therapies and complex interactions between AR signaling and the immune system means that these therapies have the potential to affect antitumor immune responses. Here, we characterize treatment responses of ADT alone and in combination with antiandrogen therapy using apalutamide (Apa) in a mouse model of Pten/Trp53-deficeint castrate-resistant prostate cancer (CRPC). Twenty-eight-week-old conditional Pten/Trp53-double knockout mice were randomized as untreated control or treated with ADT via orchidectomy for four weeks followed by vehicle or Apa therapy for an additional four weeks. While both treatments reduced tumor burden, there was no difference between treatments. Treatment responses in were further evaluated and were judged as favorable or non-favorable, relative to median tumor burden. Analysis of individual treatment responses indicated that 31.3% (5/16) of mice treated with ADT+Apa had tumor burden reductions &gt;20% (relative to the median) compared to 6.3% (1/16) in ADT, and in both instances, 37.5% (6/16) of mice treated with ADT or ADT+Apa had tumor burden increases &gt;20%. IHC showed lower nuclear/cytoplasm expression of AR in ADT+Apa treated mice and the reduction was more pronounced in favorable responders. ADT+Apa treated mice had lower gene expression levels of Ar than ADT alone and AR target genes (Fkbp5, Tmprss2, Timp4 and Nkx3.1) were decreased in ADT+Apa favorable responders whereas these target genes as well as AR-regulating genes (Myc and Igf1r, Igf1) were higher in ADT+Apa non-favorable responders. Cancer cell proliferation did not differ between treatments, but cancer glands in ADT+Apa treated mice had significantly greater IHC expression levels of cleaved caspase 3, a marker for apoptosis, and were greatest in ADT+Apa favorable responders. Levels of p-S6 ribosomal protein, a downstream target of Akt, were higher in the cancer glands of ADT+Apa but were reduced in stromal and infiltrating immune cells. Immune profiling by gene expression and flow cytometry showed enhanced macrophage involvement and reduced MDSC/granulocyte activity in ADT+Apa treated mice. There were no differences in CD8 T cell and NK cell abundance between the two cohorts, but greater cytotoxic activity was noted in all favorable responders. This study provides preclinical data that links therapeutic resistance to anti-AR signal pathways therapies in Pten/Trp53-deficeint CRPC to compensatory pathway activation and immune suppression.

Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Noriko Sako, Kazuko Sakai, Kazutoshi Fujita, Eri Banno, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Therapeutic resistance to anti-AR signal pathway therapies is related to compensatory pathway activation and immune suppression in mouse Pten/Trp53-deficient CRPC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5211.