RESUMO
Prostate cancer is frequently treated with radiotherapy. Unfortunately, aggressive radioresistant relapses can arise, and the molecular underpinnings of radioresistance are unknown. Modern clinical radiotherapy is evolving to deliver higher doses of radiation in fewer fractions (hypofractionation). We therefore analyzed genomic, transcriptomic, and proteomic data to characterize prostate cancer radioresistance in cells treated with both conventionally fractionated and hypofractionated radiotherapy. Independent of fractionation schedule, resistance to radiotherapy involved massive genomic instability and abrogation of DNA mismatch repair. Specific prostate cancer driver genes were modulated at the RNA and protein levels, with distinct protein subcellular responses to radiotherapy. Conventional fractionation led to a far more aggressive biomolecular response than hypofractionation. Testing preclinical candidates identified in cell lines, we revealed POLQ (DNA Polymerase Theta) as a radiosensitizer. POLQ-modulated radioresistance in model systems and was predictive of it in large patient cohorts. The molecular response to radiation is highly multimodal and sheds light on prostate cancer lethality. SIGNIFICANCE: Radiation is standard of care in prostate cancer. Yet, we have little understanding of its failure. We demonstrate a new paradigm that radioresistance is fractionation specific and identified POLQ as a radioresistance modulator.
Assuntos
Neoplasias da Próstata , Proteogenômica , Tolerância a Radiação , Masculino , Humanos , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Tolerância a Radiação/genética , Proteogenômica/métodos , Linhagem Celular Tumoral , DNA Polimerase teta , Instabilidade Genômica , Reparo de Erro de Pareamento de DNA , Regulação Neoplásica da Expressão Gênica , DNA Polimerase Dirigida por DNA/genética , DNA Polimerase Dirigida por DNA/metabolismo , Hipofracionamento da Dose de RadiaçãoRESUMO
PURPOSE: Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition. METHODS: We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing. RESULTS: We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for SNAI2, a key regulator of EMT reprogramming. CONCLUSION: We show that EMT characterizes acutely resistant prostate tumors and that deletion of SNAI2, a key transcriptional regulator of EMT, correlates with clinical response.
Assuntos
Antagonistas de Androgênios/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Transição Epitelial-Mesenquimal/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Fatores de Transcrição da Família Snail/genética , Idoso , Antagonistas de Androgênios/efeitos adversos , Androstenos , Anilidas , Antineoplásicos Hormonais/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Nitrilas , Oligopeptídeos , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Transdução de Sinais , Fatores de Transcrição da Família Snail/deficiência , Compostos de TosilRESUMO
Cancer is fundamentally a genomic disease caused by mutations or rearrangements in the DNA or epigenetic machinery of a patient. An emerging field in cancer treatment targets key aberrations arising from the mutational landscape of an individual patient's disease rather than employing a cancer-wide cytotoxic therapy approach. In prostate cancer in particular, where there is an observed variation in response to standard treatments between patients with disease of a similar pathological stage and grade, mutationdirected treatment may grow to be a viable tool for clinicians to tailor more effective treatments. This review will describe a number of mutations across multiple forms of cancer that have been successfully antagonised by targeted therapeutics including their identification, the development of targeted compounds to combat them and the development of resistance to these therapies. This review will continue to examine these same mutations in the treatment and management of prostate cancer; the prevalence of targetable mutations in prostate cancer, recent clinical trials of targeted-agents and the potential or limitations for their use.