RESUMEN
Despite impressive advances in the treatment of prostate cancer with various efficacious inhibitors along the androgen/androgen receptor axis, eventual development of incurable metastatic Castration-Resistant Prostate Cancer (mCRPC) is inevitable and remains a major clinical challenge. Constitutively active androgen receptor (AR) spliced variants have emerged as primary means of resistance to anti-androgens and androgen synthesis inhibitors. The alternatively spliced AR variant, ARv7, has attracted significant interest due to its constitutively active status in CRPC that drives androgen-independence. Factors that are involved in regulating ARv7 levels in CRPC are not clearly known. We recently demonstrated that a protein kinase, T-LAK cell-originated protein kinase (TOPK) level correlates with the aggressiveness of prostate cancer and its invasive behavior. In this study, we investigated whether TOPK plays a role in driving androgen-independence in prostate cancer cells. Our data demonstrate that TOPK overexpression in androgen-dependent LNCaP and VCaP induces ARv7 and drives androgen-independent growth. On the other hand, pharmacological inhibition of TOPK in androgen-independent LNCaP95 and 22Rv1 represses AR transactivation, and AR stability. In summary, this study illustrates a direct role of TOPK in regulating ARv7 and driving androgen-independence in prostate cancer cells.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Recurrencia Local de Neoplasia/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/genética , Empalme Alternativo , Antagonistas de Andrógenos/farmacología , Antagonistas de Andrógenos/uso terapéutico , Andrógenos/metabolismo , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Humanos , Concentración 50 Inhibidora , Masculino , Quinasas de Proteína Quinasa Activadas por Mitógenos/análisis , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/prevención & control , Pronóstico , Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolonas/farmacología , Quinolonas/uso terapéutico , Receptores Androgénicos/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Tiofenos/farmacología , Tiofenos/uso terapéutico , Activación Transcripcional/efectos de los fármacosRESUMEN
Malignant peripheral nerve sheath tumor (MPNST) is a rare, aggressive soft-tissue sarcoma with a poor prognosis and is insensitive to immune checkpoint blockade (ICB) therapy. Loss-of-function of the histone modifying polycomb repressive complex 2 (PRC2) components, EED or SUZ12, is one of the main mechanisms of malignant transformation. In a murine model of MPNST, PRC2-loss tumors have an "immune desert" phenotype and intratumoral (IT) delivery immunogenic modified vaccinia virus Ankara (MVA) sensitized the PRC2-loss tumors to ICB. Here we show that IT MQ833, a second-generation recombinant modified vaccinia virus Ankara virus, results in neutrophil recruitment and activation and neutrophil-dependent tumor killing in the MPNST model. MQ833 was engineered by deleting three viral immune evasion genes, E5R, E3L, and WR199, and expressing three transgenes, including the two membrane-bound Flt3L and OX40L, and IL-12 with an extracellular matrix anchoring signal. Furthermore, we explored strategies to enhance anti-tumor effects of MQ833 by co-administration of granulocyte colony-stimulating factor (G-CSF).