thiohydantoins and Cell-Transformation--Neoplastic

Resistance to AR signaling inhibitors (ARSis) in a subset of metastatic castration-resistant prostate cancers (mCRPCs) occurs with the emergence of AR- neuroendocrine prostate cancer (NEPC) coupled with mutations/deletions in PTEN, TP53, and RB1 and the overexpression of DNMTs, EZH2, and/or SOX2. To resolve whether the lack of AR is the driving factor for the emergence of the NE phenotype, molecular, cell, and tumor biology analyses were performed on 23 xenografts derived from patients with PC, recapitulating the full spectrum of genetic alterations proposed to drive NE differentiation. Additionally, phenotypic response to CRISPR/Cas9-mediated AR KO in AR+ CRPC cells was evaluated. These analyses document that (a) ARSi-resistant NEPC developed without androgen deprivation treatment; (b) ARS in ARSi-resistant AR+/NE+ double-positive "amphicrine" mCRPCs did not suppress NE differentiation; (c) the lack of AR expression did not necessitate acquiring a NE phenotype, despite concomitant mutations/deletions in PTEN and TP53, and the loss of RB1 but occurred via emergence of an AR-/NE- double-negative PC (DNPC); (d) despite DNPC cells having homogeneous genetic driver mutations, they were phenotypically heterogeneous, expressing basal lineage markers alone or in combination with luminal lineage markers; and (e) AR loss was associated with AR promoter hypermethylation in NEPCs but not in DNPCs.

Topics: Abiraterone Acetate; Animals; Antineoplastic Agents; Benzamides; Carcinoma, Neuroendocrine; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Male; Mice; Neoplasm Transplantation; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; PTEN Phosphohydrolase; Receptors, Androgen; Retinoblastoma Binding Proteins; SOXB1 Transcription Factors; Thiohydantoins; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases

Immune escape is a crucial feature of cancer progression about which little is known. Elevation of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) in tumor cells can facilitate immune escape. Not known is how IDO becomes elevated or whether IDO inhibitors will be useful for cancer treatment. Here we show that IDO is under genetic control of Bin1, which is attenuated in many human malignancies. Mouse knockout studies indicate that Bin1 loss elevates the STAT1- and NF-kappaB-dependent expression of IDO, driving escape of oncogenically transformed cells from T cell-dependent antitumor immunity. In MMTV-Neu mice, an established breast cancer model, we show that small-molecule inhibitors of IDO cooperate with cytotoxic agents to elicit regression of established tumors refractory to single-agent therapy. Our findings suggest that Bin1 loss promotes immune escape in cancer by deregulating IDO and that IDO inhibitors may improve responses to cancer chemotherapy.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Transformation, Neoplastic; DNA-Binding Proteins; Drug Synergism; Enzyme Inhibitors; Indoleamine-Pyrrole 2,3,-Dioxygenase; Indoles; Interferon-gamma; Mammary Neoplasms, Experimental; Mice; Molecular Sequence Data; Nerve Tissue Proteins; NF-kappa B; Paclitaxel; Rats; STAT1 Transcription Factor; Thiohydantoins; Trans-Activators; Tryptophan Oxygenase; Tumor Escape; Tumor Suppressor Proteins