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 the PIK3CA gene, 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, PIK3CA mutations 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 in APC and PIK3CA
Colorectal cancer spheroids with Apc and Pik3ca mutations 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 with Apc and Pik3ca-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 and P = 0.03, respectively). This response was also confirmed with
18F-FDG microPET/CT imaging.Implications: Spheroid models and transgenic mice suggest that dual PI3K/mTOR inhibition is a potential treatment strategy for APC and PIK3CA-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.