mln-8237 and Carcinogenesis

Neuroendocrine (NE) cancers are a diverse group of neoplasms typically diagnosed and treated on the basis of their site of origin. This Perspective focuses on advances in our understanding of the tumorigenesis and treatment of poorly differentiated neuroendocrine tumors. Recent evidence from sequencing indicates that, although neuroendocrine tumors can arise de novo, they can also develop as a result of lineage plasticity in response to pressure from targeted therapies. We discuss the shared genomic alterations of these tumors independently of their site of origin, and we explore potential therapeutic strategies on the basis of recent biological findings.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Azepines; Benzodiazepines; Carcinogenesis; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Cell Differentiation; Cell Lineage; Cell Plasticity; Colonic Neoplasms; Disease Progression; Epigenesis, Genetic; Esophageal Neoplasms; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Molecular Targeted Therapy; Neoplasms, Glandular and Epithelial; Neuroendocrine Tumors; Ovarian Neoplasms; Prostatic Neoplasms; Proto-Oncogene Proteins c-met; Proto-Oncogene Proteins c-myc; Pyrimidines; Retinoblastoma Binding Proteins; Triazoles; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases; Urinary Bladder Neoplasms; Uterine Cervical Neoplasms

The high prevalence of KRAS mutations and importance of the RalGEF-Ral pathway downstream of activated K-ras in pancreatic ductal adenocarcinoma (PDAC) emphasize the importance of identifying novel methods by which to therapeutically target these pathways. It was recently demonstrated that phosphorylation of RalA S194 by Aurora A kinase (AAK) is critical for PDAC tumorigenesis. We sought to evaluate the AAK-selective inhibitor MLN8237 as a potential indirect anti-RalA-targeted therapy for PDAC. We used a site-specific phospho-S194 RalA antibody and determined that RalA S194 phosphorylation levels were elevated in a subset of PDAC cell lines and human tumors relative to unmatched normal controls. Effects of MLN8237 on anchorage-independent growth in PDAC cell lines and growth of patient-derived xenografts (PDX) were variable, with a subset of cell lines and PDX showing sensitivity. Surprisingly, RalA S194 phosphorylation levels in PDAC cell lines or PDX tumors did not correlate with MLN8237 responsiveness. However, we identified Ki67 as a possible early predictive biomarker for response to MLN8237 in PDAC. These results indicate that MLN8237 treatment may be effective for a subset of patients with PDAC independent of RalA S194 phosphorylation. Ki67 may be an effective pharmacodynamic biomarker to identify response early in the course of treatment.

Topics: Aurora Kinase A; Azepines; Biomarkers, Tumor; Carcinogenesis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Humans; Ki-67 Antigen; Mutation; Phosphorylation; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Pyrimidines; ral GTP-Binding Proteins; ras Proteins

Chronic inflammation contributes to the pathogenesis of gastric tumorigenesis. The aurora kinase A (AURKA) gene is frequently amplified and overexpressed in gastrointestinal cancers. We investigated the roles of AURKA in inflammation and gastric tumorigenesis.. We used quantitative real-time reverse transcription polymerase chain reaction, immunofluorescence, immunohistochemistry, luciferase reporter, immunoblot, co-immunoprecipitation, and in vitro kinase assays to analyze AGS and MKN28 gastric cancer cells. We also analyzed Tff1(-/-) mice, growth of tumor xenografts, and human tissues.. We correlated increased expression of AURKA with increased levels of tumor necrosis factor-α and inflammation in the gastric mucosa of Tff1(-/-) mice (r = 0.62; P = .0001). MLN8237, an investigational small-molecule selective inhibitor of AURKA, reduced nuclear staining of nuclear factor-κB (NF-κB) p65 in human gastric cancer samples and mouse epithelial cells, suppressed NF-κB reporter activity, and reduced expression of NF-κB target genes that regulate inflammation and cell survival. Inhibition of AURKA also reduced growth of xenograft tumors from human gastric cancer cells in mice and reversed the development of gastric tumors in Tff1(-/-) mice. AURKA was found to regulate NF-κB activity by binding directly and phosphorylating IκBα in cells. Premalignant and malignant lesions from the gastric mucosa of patients had increased levels of AURKA protein and nuclear NF-κB, compared with healthy gastric tissue.. In analyses of gastric cancer cell lines, human tissue samples, and mouse models, we found AURKA to be up-regulated during chronic inflammation to promote activation of NF-κB and tumorigenesis. AURKA inhibitors might be developed as therapeutic agents for gastric cancer.

Topics: Adenocarcinoma; Animals; Aurora Kinase A; Azepines; Carcinogenesis; Cell Line, Tumor; Disease Models, Animal; Female; Gastric Mucosa; Heterografts; Humans; In Vitro Techniques; Inflammation; Mice, Knockout; Mice, Nude; NF-kappa B; Peptides; Phosphorylation; Protein Kinase Inhibitors; Pyrimidines; Stomach Neoplasms; Trefoil Factor-1; Up-Regulation