Genotype directed therapy in murine mismatch repair deficient tumors.
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.
Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
Melanie H
MH
Kucherlapati
Shadi
S
Esfahani
Peiman
P
Habibollahi
Junning
J
Wang
Eric R
ER
Still
Roderick T
RT
Bronson
Umar
U
Mahmood
Raju S
RS
Kucherlapati
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D053843:DNA Mismatch Repair / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D015321:Gene Rearrangement / Q000187:drug effects; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D019426:Integrases / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D051718:MutS Homolog 2 Protein / Q000172:deficiency / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D007093:Imidazoles; D019426:Integrases; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; D051153:Wnt Proteins; C045073:Cre recombinase; C497172:MSH2 protein, human; C531198:dactolisib