Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas.

Abstract

The PI3K (phosphatidylinositol-3-kinase)/mTOR (mammalian target of rapamycin) pathway is frequently activated in endometrial cancer through various PI3K/AKT-activating genetic alterations. We examined the antitumor effect of NVP-BEZ235-a dual PI3K/mTOR inhibitor-and RAD001-an mTOR inhibitor-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 (PD98059 or UO126) in cell lines with K-Ras alterations (mutations or amplification). PTEN mutant cell lines without K-Ras alterations (n = 9) were more sensitive to both RAD001 and NVP-BEZ235 than were cell lines with K-Ras alterations (n = 4). Dose-dependent growth suppression was more drastically induced by NVP-BEZ235 than by RAD001 in the sensitive cell lines. G1 arrest was induced by NVP-BEZ235 in a dose-dependent manner. We observed in vivo antitumor activity of both RAD001 and NVP-BEZ235 in nude mice. The presence of a MEK inhibitor, PD98059 or UO126, sensitized the K-Ras mutant cells to NVP-BEZ235. Robust growth suppression by NVP-BEZ235 suggests that a dual PI3K/mTOR inhibitor is a promising therapeutic for endometrial carcinomas. Our data suggest that mutational statuses of PTEN and K-Ras might be useful predictors of sensitivity to NVP-BEZ235 in certain endometrial carcinomas.

The PI3K/AKT/mTOR Pathway as a Therapeutic Target in Endometrial Cancer

“…Indeed, in endometrial cancer cell lines, KRAS mutations segregated with reduced sensitivity to everolimus and to NVP-BEZ235. Combination of NVP-BEZ235 with the MEK inhibitor PD98059, however, synergistically suppressed proliferation in endometrial cancer cell lines with PTEN and KRAS mutations (28). Contrary to these in vitro studies, a phase II clinical trial in 28 patients with endometrial cancer found no correlation between KRAS mutations and response to everolimus (68).…”

“…Greatest sensitivity to NVP-BEZ235 was observed in endometrial cancer cells with PIK3CA and/or PTEN mutations (28,29). In addition, NVP-BEZ35 significantly suppressed tumor growth in mice inoculated with the endometrial cell lines AN3CA or Hec-59, which contain PTEN and PTEN/PIK3CA mutations, respectively.…”

“…mTORC1 inhibitors currently in clinical development include everolimus, temsirolimus, and ridaforolimus. Recently, everolimus and temsirolimus showed antitumor activity in endometrial cancer cell lines, with greatest sensitivity in cells with PIK3CA and/or PTEN mutations (28)(29)(30). Furthermore, everolimus reduced progression of endometrial hyperplasia in a PTEN heterozygous mouse model (31), and repressed tumor growth in mouse xenograft models harboring endometrial cancer cells with loss of PTEN and/or PIK3CA mutations (32).…”