RESUMO
TMPRSS2-ERG rearrangement is a genetic alteration exclusive to prostate cancer, associated with taxane resistance in preclinical models. Its detection in blood samples of metastatic resistant prostate cancer (mCRPC) patients may indicate the presence of circulating tumour cells with this genetic alteration and may predict taxane resistance. To test this hypothesis, we evaluated TMPRSS2-ERG expression using quantitative reverse transcription polymerase chain reaction in peripheral blood mononuclear cells and tumour tissue from mCPRC patients treated with taxanes. We examined peripheral blood mononuclear cells from 24 healthy controls, 50 patients treated with docetaxel, and 22 with cabazitaxel. TMPRSS2-ERG was detected in 0%, 16%, and 22.7% of them, respectively. In docetaxel-treated patients TMPRSS2-ERG detection correlated with lower prostatic-specific antigen (PSA) response rate (12.5% vs 68.3%, p=0.005), PSA-progression-free survival (PFS; 3.1 mo vs 7.5 mo, p<0.001), clinical/radiological-PFS (3.1 mo vs 8.2 mo, p<0.001), and it was independently associated with PSA-PFS (hazard ratio 3.7; p=0.009) and clinical/radiological-PFS (hazard ratio 6.3; p<0.001). Moreover, TMPRSS2-ERG also predicted low PSA-PFS to cabazitaxel. At progression, a switch from negative to positive TMPRSS2-ERG was observed in 41% of patients with undetected TMPRSS2-ERG at the baseline sample. Tissue TMPRSS2-ERG expression correlated with lower PSA-PFS (p=0.02) to docetaxel. Our findings support the potential role of TMPRSS2-ERG detection as a biomarker to tailor treatment strategies. PATIENT SUMMARY: Taxanes are the most active chemotherapy agents in metastatic resistant prostate cancer. However, not all patients respond to this therapy. In the present study we show that the detection of TMPRSS2-ERG in blood from metastatic resistant prostate cancer patients predicts resistance to docetaxel and it may be useful to select treatment and to avoid possible toxicities in refractory patients.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão Oncogênica/genética , Próstata , Neoplasias de Próstata Resistentes à Castração , Taxoides/administração & dosagem , Idoso , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/genética , Intervalo Livre de Doença , Docetaxel , Humanos , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Próstata/diagnóstico por imagem , Próstata/patologia , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Resultado do TratamentoRESUMO
Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel + androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-κB transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44(+) subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44(+) subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evidence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Neoplasias da Próstata/patologia , Taxoides/farmacologia , Idoso , Linhagem Celular Tumoral , Análise por Conglomerados , Docetaxel , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Fatores de Transcrição/metabolismo , Resultado do Tratamento , Homeobox 1 de Ligação a E-box em Dedo de ZincoRESUMO
Prostate cancer cells express the androgen receptor (AR) and need the presence of androgens to survive. Androgen suppression is the gold standard first-line therapy for metastatic disease. Almost all prostate cancer patients initially respond to hormonal therapy, but most of them gradually develop castration-resistant progression. Recent evidence has shown that progression at the castration resistant prostate cancer (CRPC) stage is often mediated by AR signalling. Importantly, subsequent AR androgen inhibition, by abiraterone acetate or enzalutamide, has shown to improve patients' survival. Several mechanisms that enhance AR signalling in an androgen-depleted environment have been elucidated:(1) AR mutations that allow activation by low androgen levels or by other endogenous steroids, (2) AR amplification and/or overexpression,(3)increased local intracrine synthesis of androgens, (4) changes in AR cofactors and (5) cross-talk with cytokines and growth factors. Today, there are under development a number of novel agents targeting the AR signaling pathway. This article reviews the postulated mechanisms of AR-driven resistance to androgen suppression that have contributed to the development of new hormonal therapeutic strategies in prostate cancer.
Assuntos
Biologia Molecular , Orquiectomia , Neoplasias da Próstata/genética , Neoplasias da Próstata/cirurgia , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Androgênios/biossíntese , Animais , Progressão da Doença , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/genética , Transdução de Sinais/fisiologia , Tubulina (Proteína)/efeitos dos fármacosRESUMO
Las células del cáncer de próstata expresan receptos de andrógenos (RA) y necesitan la presencia de andrógenos para sobrevivir. La supresión androgénica es el patrón oro en el tratamiento de primera línea de la enfermedad metastática. Casi todos los pacientes con cáncer de próstata responden inicialmente al tratamiento, pero la mayoría de ellos desarrollan gradualmente progresión resistente a castración. La evidencia reciente ha demostrado que la progresión en el estadio de cáncer resistente a castración esta mediada frecuentemente por la señalización del RA. De una manera importante, la inhibición androgénica posterior del RA, por medio de abiraterona o enzalutamida, ha demostrado mejorar la supervivencia de los pacientes. Se han elucidado varios mecanismos que mejoran la señalización del RA en un entorno reducido de andrógenos: (1) mutaciones del RA que permiten la activación por niveles de andrógenos bajos o por otros esteroides endógenos, (2) amplificación y/o sobreexpresión del RA , (3) síntesis de andrógenos local intracrina aumentada, (4) cambios en cofactores del RA e (5) intercomunicación con citokinas y factores de crecimiento. Hoy, están en desarrollo varios nuevos agentes dirigidos a la vía de señalización del RA. Este artículo revisa los mecanismos postulados de resistencia a la deprivación androgénica dirigida por el RA que han contribuido al desarrollo de nuevas estrategias terapéuticas hormonales en cáncer de próstata (AU)
Prostate cancer cells express the androgen receptor (AR) and need the presence of androgens to survive. Androgen suppression is the gold standard first-line therapy for metastatic disease. Almost all prostate cancer patients initially respond to hormonal therapy, but most of them gradually develop castration-resistant progression. Recent evidence has shown that progression at the castration resistant prostate cancer (CRPC) stage is often mediated by AR signalling. Importantly, subsequent AR androgen inhibition, by abiraterone acetate or enzalutamide, has shown to improve patients´ survival. Several mechanisms that enhance AR signaling in an androgen-depleted environment have been elucidated: (1) AR mutations that allow activation by low androgen levels or by other endogenous steroids, (2) AR amplification and/or overexpression, (3) increased local intracrine synthesis of androgens, (4) changes in AR cofactors and (5) cross-talk with cytokines and growth factors. Today, there are under development a number of novel agents targeting the AR signaling pathway. This article reviews the postulated mechanisms of AR-driven resistance to androgen suppression that have contributed to the development of new hormonal therapeutic strategies in prostate cancer (AU)
