Genotype-Dependent Efficacy of a Dual PI3K/mTOR Inhibitor, NVP-BEZ235, and an mTOR Inhibitor, RAD001, in Endometrial Carcinomas

5110 Background: PI3K (phosphatidylinositol-3-kinase) /mTOR (mammalian target of rapamycin) pathway is frequently activated in endometrial cancer through various PI3K/AKT activating genetic alterations, including mutations in PTEN, PIK3CA, and K-Ras. We evaluated the activity of a dual PI3K/mTOR.inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial cancer cell lines. METHODS We examined anti-tumor effect of RAD001 and NVP-BEZ235 in 13 endometrial cancer cell lines, all of which possess one or more alterations in PTEN, PIK3CA and K-Ras. We also combined these compounds with a MAPK pathway inhibitor in cell lines with K-Rasalterations (mutations or amplification). RESULTS PTEN mutant cell lines without K-Rasalterations (n=9) were more sensitive to both RAD001 and NVP-BEZ235 than the other cell lines with K-Rasalterations (n=4). NVP-BEZ235 showed lower IC50 values than RAD001 in eight of the nine sensitive cell lines, and G1 arrest was more effectively induced by NVP-BEZ235 than RAD001. We observed in vivo anti-tumor activity of both RAD001 and NVP-BEZ235 at a tolerated dose in nude mice. Combination of NVP-BEZ235 with a MEK inhibitor PD98059 and UO126 synergistically suppressed the proliferation in cells with K-Rasalterations. CONCLUSIONS Robust growth suppression by NVP-BEZ235 suggests that a dual PI3K/mTOR inhibitor, such as NVP-BEZ235, is a promising therapeutics in endometrial carcinomas. Our data suggest that presence of PTEN mutations without K-Ras alterations may be a good predictive biomarker to NVP-BEZ235 in certain endometrial carcinomas. Combination of a PI3K/mTOR inhibitor with a MEK inhibitor PD98059 and UO126 might be effective to the tumors with K-Ras alterations.