The effects of LY294002, a PI3K inhibitor, on cell growth were examined to elucidate the role of the PI3K-Akt/protein kinase B (PKB) pathway in colon cancer.
These results show that almost all the colon cancer-associated PIK3CA mutations are functionally active so that they are likely to be involved in carcinogenesis.
PI3K pathway components p85alpha and Akt2 were highly expressed in glandular elements of colon cancers, with a correlation between staining intensity and clinical stage; PTEN expression was decreased in the colon cancers of all stages.
We screened the colon cancer cell lines previously established in our laboratory for PIK3CA mutations and found that four of them harbored gain of function mutations.
Collectively, these results indicate that DCT-induced activation of post-EGFR PI3K/Akt signaling stimulates both colon cancer cell survival and proliferation.
Using pharmacological inhibitors of pathways downstream of K-RAS, we could show that the PI3K and p42/44 MAPK pathways play an important role in the induction of KLK6 in mutant K-RAS-expressing colon cancer cells.
Among patients with KRAS wild-type tumors, the presence of PIK3CA mutation was associated with a significant increase in colon cancer-specific mortality (HR = 3.80; 95% CI, 1.56 to 9.27).
HCT-116 cells, a human model of colon cancer, which are highly metastatic and undifferentiated, were treated with LY294002, a specific inhibitor of PI3K.
To define the inhibitory and pro-apoptotic effects of the two PI3K inhibitors BEZ235 and BKM120 in three human colon cancer (HT-29, HCT-116 and DLD-1) and three gastric cancer (NCI-n87, AGS and MKN-45), cell lines with different PIK3CA gene mutation status were used.
This first demonstration of therapeutic efficacy against Kras-mutant colon cancer suggests that Hu-r-βGBP may also be therapeutically effective against other cancers harboring activating Ras mutations as well as PIK3CA mutations.
PI3K pathway mutation is prominent in proximal colon cancers, with PIK3CA exon 20 and PTEN mutations associated with features of the sessile-serrated pathway (MSI-H/CIMP-H/BRAF(mut)), and PIK3CA exon 9 (and to a lesser extent exon 20) mutation associated with features of the traditional serrated pathway (CIMP-L/KRAS(mut)) of tumorigenesis.
We verified multiple associations between oncogenic mutations and determined clinicopathological tumor features (1) EGFR A13_deletions are associated with right colon carcinoma (P<0.005), mucinous histotype (P=0.042), G3 grading (P=0.024), and MSI status (P<0.005); (2) PIK3CA mutations are related mucinous histotype (P=0.021); (3) KRAS(G12) and KRAS(G13) mutations are correlated, respectively, with the left and right colon cancer development (P<0.005), and finally (4) MSI is associated with right colon tumors (P<0.005).
To clarify clinical outcome associations of combined MSI/BRAF subgroups, we investigated survival in 1253 rectal and colon cancer patients within the Nurses' Health Study and Health Professionals Follow-up Study with available data on clinical and other molecular features, including CIMP, LINE-1 hypomethylation, and KRAS and PIK3CA mutations.