azd-6244 and Carcinoma--Pancreatic-Ductal

Activating mutations in the proto-oncogene KRAS are a hallmark of pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy with few effective therapeutic options. Despite efforts to develop KRAS-targeted drugs, the absolute dependence of PDAC cells on KRAS remains incompletely understood. Here we model complete KRAS inhibition using CRISPR/Cas-mediated genome editing and demonstrate that KRAS is dispensable in a subset of human and mouse PDAC cells. Remarkably, nearly all KRAS deficient cells exhibit phosphoinositide 3-kinase (PI3K)-dependent mitogen-activated protein kinase (MAPK) signaling and induced sensitivity to PI3K inhibitors. Furthermore, comparison of gene expression profiles of PDAC cells retaining or lacking KRAS reveal a role of KRAS in the suppression of metastasis-related genes. Collectively, these data underscore the potential for PDAC resistance to even the very best KRAS inhibitors and provide insights into mechanisms of response and resistance to KRAS inhibition.

Topics: Animals; Antineoplastic Agents; Benzimidazoles; Carcinoma, Pancreatic Ductal; DNA Copy Number Variations; Humans; Immunoblotting; Indazoles; Mice; Morpholines; Pancreatic Neoplasms; Phenylurea Compounds; Piperidines; Proto-Oncogene Mas; Proto-Oncogene Proteins p21(ras); Purines; Pyrimidines; Pyrimidinones; Quinazolinones; Sulfonamides; Thiazoles

Improved therapeutic approaches are needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). As dual MEK and PI3K inhibition is presently being used in clinical trials for patients with PDAC, we sought to test the efficacy of combined targeting of these pathways in PDAC using both in vitro drug screens and genetically engineered mouse models (GEMM).. We performed high-throughput screening of >500 human cancer cell lines (including 46 PDAC lines), for sensitivity to 50 clinically relevant compounds, including MEK and PI3K inhibitors. We tested the top hit in the screen, the MEK1/2 inhibitor, AZD6244, for efficacy alone or in combination with the PI3K inhibitors, BKM120 or GDC-0941, in a Kras(G12D)-driven GEMM that recapitulates the histopathogenesis of human PDAC.. In vitro screens revealed that PDAC cell lines are relatively resistant to single-agent therapies. The response profile to the MEK1/2 inhibitor, AZD6244, was an outlier, showing the highest selective efficacy in PDAC. Although MEK inhibition alone was mainly cytostatic, apoptosis was induced when combined with PI3K inhibitors (BKM120 or GDC-0941). When tested in a PDAC GEMM and compared with the single agents or vehicle controls, the combination delayed tumor formation in the setting of prevention and extended survival when used to treat advanced tumors, although no durable responses were observed.. Our studies point to important contributions of MEK and PI3K signaling to PDAC pathogenesis and suggest that dual targeting of these pathways may provide benefit in some patients with PDAC. Clin Cancer Res; 21(2); 396-404. ©2014 AACR.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Benzimidazoles; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Disease Models, Animal; Drug Screening Assays, Antitumor; Drug Synergism; Erlotinib Hydrochloride; Humans; MAP Kinase Kinase Kinases; Mice, Transgenic; Morpholines; Pancreatic Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Quinazolines

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzimidazoles; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Pancreatic Neoplasms; Protein Serine-Threonine Kinases; Ribosomal Protein S6; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays