Dual PI3K/mTOR Inhibition in Colorectal Cancers withAPCandPIK3CAMutations.
Therapeutic targeting of the PI3K pathway is an active area of research in multiple cancer types, including breast and endometrial cancers. This pathway is commonly altered in cancer and plays an integral role in numerous vital cellular functions. Mutations in thePIK3CAgene, resulting in a constitutively active form of PI3K, often occur in colorectal cancer, though the population of patients who would benefit from targeting this pathway has yet to be identified. In human colorectal cancers,PIK3CAmutations most commonly occur concomitantly with loss of adenomatous polyposis coli (APC). Here, treatment strategies are investigated that target the PI3K pathway in colon cancers with mutations inAPCandPIK3CAColorectal cancer spheroids withApcandPik3camutations were generated and characterized confirming that these cultures represent the tumors from which they were derived. Pan and alpha isomer-specific PI3K inhibitors did not induce a significant treatment response, whereas the dual PI3K/mTOR inhibitors BEZ235 and LY3023414 induced a dramatic treatment response through decreased cellular proliferation and increased differentiation. The significant treatment responses were confirmed in mice withApcandPik3ca-mutant colon cancers as measured using endoscopy with a reduction in median lumen occlusion of 53% with BEZ235 and a 24% reduction with LY3023414 compared with an increase of 53% in controls (P< 0.001 andP= 0.03, respectively). This response was also confirmed with18F-FDG microPET/CT imaging.Implications:Spheroid models and transgenic mice suggest that dual PI3K/mTOR inhibition is a potential treatment strategy forAPCandPIK3CA-mutant colorectal cancers. Thus, further clinical studies of dual PI3K/mTOR inhibitors are warranted in colorectal cancers with these mutations.Mol Cancer Res; 15(3); 1-11. ©2016 AACR.
Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
Tyler M
TM
Foley
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Susan N
SN
Payne
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
Cheri A
CA
Pasch
Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
Alex E
AE
Yueh
Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
Dana R
DR
Van De Hey
Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
Demetra P
DP
Korkos
McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin.
Linda
L
Clipson
Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
Molly E
ME
Maher
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.|Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin.|William S Middleton Memorial Veterans Hospital, Madison, Wisconsin.
Kristina A
KA
Matkowskyj
Departments of Statistics and of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin.
Michael A
MA
Newton
Division of Hematology and Oncology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin. ddeming@medicine.wisc.edu.|University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.|McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin.|William S Middleton Memorial Veterans Hospital, Madison, Wisconsin.
Dustin A
DA
Deming