Genotype directed therapy in murine mismatch repair deficient tumors

• Published in: PloS one 2013-07, Vol.8 (7), p.e68817
• Main Authors: Kucherlapati, Melanie H, Esfahani, Shadi, Habibollahi, Peiman, Wang, Junning, Still, Eric R, Bronson, Roderick T, Mahmood, Umar, Kucherlapati, Raju S
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animal models; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Apoptosis - drug effects; Biology; Breast cancer; Cancer; Catheters; Cell Line, Tumor; Clinical trials; Colon cancer; Colorectal cancer; Cyclin D1; Disease Models, Animal; Disease Progression; DNA Mismatch Repair - genetics; Drugs; Endoscopes; Endoscopy; Gastrointestinal diseases; Gene Rearrangement - drug effects; Genetic aspects; Genetics; Genotype; Hospitals; Humans; Imidazoles - pharmacology; Imidazoles - therapeutic use; Inhibitors; Integrases - metabolism; Intestinal Neoplasms - drug therapy; Intestinal Neoplasms - enzymology; Intestinal Neoplasms - genetics; Intestinal Neoplasms - pathology; Intestine; Kinases; Laboratory animals; MAP kinase; MAP Kinase Signaling System - drug effects; Medical research; Medical schools; Medicine; Metabolism; Metastasis; Mice; Mismatch repair; MSH2 protein; Mutation; MutS Homolog 2 Protein - deficiency; MutS Homolog 2 Protein - metabolism; Neoplasm Proteins - metabolism; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; Neoplasms - therapy; Nuclear medicine; Pathology; Phosphatidylinositol 3-Kinases - metabolism; Positron emission; Positron emission tomography; PTEN protein; Quinolines - pharmacology; Quinolines - therapeutic use; Rodents; Signal transduction; Signaling; Substance abuse treatment; Surgery; Therapy; Tomography; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumor cell lines; Tumors; Up-Regulation - drug effects; Wnt protein; Wnt Proteins - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0068817

The PI3K/AKT/mTOR pathway has frequently been found activated in human tumors. We show that in addition to Wnt signaling dysfunction, the PI3K/AKT/mTOR pathway is often upregulated in mouse Msh2(-/-) initiated intestinal tumors. NVP-BEZ235 is a dual PI3K/mTOR inhibitor toxic to many cancer cell lines and currently involved in clinical trials. We have treated two mouse models involving Msh2 that develop small intestinal and/or colonic tumors with NVP-BEZ235, and a subset of animals with NVP-BEZ235 and MEK inhibitor ADZ4266. The disease phenotype has been followed with pathology, (18)F FDG PET imaging, and endoscopy. Intestinal adenocarcinomas are significantly decreased in multiplicity by both drug regimens. The majority of tumors treated with combined therapy regress significantly, while a small number of highly progressed tumors persist. We have examined PTEN, AKT, MEK 1&2, MAPK, S6K, mTOR, PDPK1, and Cyclin D1 and find variable alterations that include downregulation of PTEN, upregulation of AKT and changes in its phosphorylated forms, upregulation of pMEK 1&2, p42p44MAPK, pS6K, and Cyclin D1. Apoptosis has been found intact in some tumors and not in others. Our data indicate that NVP-BEZ235 alone and in combination with ADZ4266 are effective in treating a proportion of colorectal cancers, but that highly progressed resistant tumors grow in the presence of the drugs. Pathways upregulated in some resistant tumors also include PDPK1, suggesting that metabolic inhibitors may also be useful in treating these tumors.