Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines.

522 Background: New targeted agents against tyrosine kinases expand the standard therapy in oncology. However, tumor resistance is still a challenge, particularly induced by mutations in growth-related signalling cascades. 20% and 10% of patients with human colon and gastric cancer carry PI3K mutations and do not react to receptor blocking therapies. Recently, selective tyrosine kinase inhibitors have been generated which block PI3K signalling pathways in tumor cells. Their therapeutically role has not yet been clarified.

METHODS: To define inhibitory and pro-apoptotic effects of the 2 PI3K inhibitors BEZ235 and BKM120 3 human colon cancer (HT-29, HCT-116, DLD-1) and 3 gastric cancer cell lines (NCI-n87, AGS, MKN-45) with different PIK3CA mutation status were used. First, viability, apoptosis and caspase assays were performed during incubation with inhibitors alone or combined with cytotoxic agents. Second, molecular consequences for cell cycle and the signalling pathways were analysed by defining the protein levels by FACS and Western blot.

RESULTS: Both PI3K inhibitors BEZ235 and BKM120 induced concentration dependently a significant reduction in viability and an increase in apoptotic death, while mutated cells reacted more sensitive to treatment. BKM120 had a higher efficiency than the dual PI3K/mTOR inhibitor BEZ235. BEZ235 alone caused a G1 arrest in tumor cells. In contrast, BKM120 induced a G2 shift in all gastrointestinal cancer cells. There was a clear downregulation in AKT signalling, and for BEZ235 an additional inhibition of mTOR pathway. Furthermore, BEZ235 caused synergistic induction of apoptosis combined with irinotecan in colon cancer. Combinations with 5-fluoruracil and the 2 substances induced additive apoptotic effects. Human gastric cancer cells were less sensitive to BEZ235 and BKM120.

CONCLUSIONS: In general, we found higher pro-apoptotic effects for all cell lines and in special cases a better response of resistant mutant cells. Our data support the clinical development of these PI3K inhibitors BEZ235 and BKM120 as potential targeting agents for patients with different wild-type or mutated gastrointestinal cancer cells.