RESUMEN
PURPOSE: Although high-grade serous ovarian cancer (HGSOC) is frequently chemoresponsive, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival (PFS) of less than 6 months. Validated predictive biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of intrinsic resistance. Our aim was to identify DNA methylation biomarkers of poor response to chemotherapy and demonstrate involvement of the associated gene in platinum drug cell sensitivity. EXPERIMENTAL DESIGN: DNA methylation was investigated in independent tumor cohorts using Illumina HumanMethylation arrays and gene expression by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction and siRNA knockdown of ovarian cancer cell lines. RESULTS: CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in independent cohorts of HGSOC patients, which recur by 6 months compared with after 12 months (P < 0.05, q < 0.05, n = 78), have poor RECIST response (P < 0.05, q < 0.05, n = 61), and are associated with PFS in an independent cohort (n = 146). A decrease in methylation at these CpG sites correlates with decreased MSX1 gene expression. MSX1 expression is associated with PFS (HR, 0.92; 95% CI, 0.85-0.99; P = 0.029; n = 309). Cisplatin-resistant ovarian cancer cell lines have reduced MSX1 expression, and MSX1 overexpression leads to cisplatin sensitization, increased apoptosis, and increased cisplatin-induced p21 expression. CONCLUSIONS: Hypomethylation of CpG sites within the MSX1 gene is associated with resistant HGSOC disease at presentation and identifies expression of MSX1 as conferring platinum drug sensitivity. Clin Cancer Res; 22(12); 3097-104. ©2016 AACR.
Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Cisplatino/uso terapéutico , Metilación de ADN/genética , Resistencia a Antineoplásicos/genética , Factor de Transcripción MSX1/genética , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Carcinoma Epitelial de Ovario , Línea Celular Tumoral , Proliferación Celular/genética , Islas de CpG/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Ováricas/mortalidad , Interferencia de ARN , ARN Interferente Pequeño/genéticaRESUMEN
Despite their long recognised pivotal roles in immunological responses, Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) are now seen as important players in cancer development and progression. Indeed, mutations in the JAKs are often found in myeloproliferative disorders (MPDs) and leukaemia, and the constitutive phosphorylation of STATs is a common occurrence in many solid and blood cancer cell lines and primary tumour specimens. More recently, we have also shown that JAKs likely have additional roles in promoting drug resistance in several cancer cell types. JAKs and STATs are thus molecules that may serve as useful targets in the clinic. This review will summarise studies that support this notion.