The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer.

Abstract

PURPOSE:

To examine the in vitro and in vivo efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type colorectal cancer (CRC).

EXPERIMENTAL DESIGN:

PIK3CA mutant and wild-type human CRC cell lines were treated in vitro with NVP-BEZ235, and the resulting effects on proliferation, apoptosis, and signaling were assessed. Colonic tumors from a genetically engineered mouse (GEM) model for sporadic wild-type PIK3CA CRC were treated in vivo with NVP-BEZ235. The resulting effects on macroscopic tumor growth/regression, proliferation, apoptosis, angiogenesis, and signaling were examined.

RESULTS:

In vitro treatment of CRC cell lines with NVP-BEZ235 resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (median IC(50) = 9.0-14.3 nM). Similar effects were seen in paired isogenic CRC cell lines that differed only in the presence or absence of an activating PIK3CA mutant allele. In vivo treatment of colonic tumor-bearing mice with NVP-BEZ235 resulted in transient PI3K inhibition and sustained blockade of mTORC1/mTORC2 signaling. Longitudinal tumor surveillance by optical colonoscopy demonstrated a 97% increase in tumor size in control mice (p = 0.01) vs. a 43% decrease (p = 0.008) in treated mice. Ex vivo analysis of the NVP-BEZ235-treated tumors demonstrated a 56% decrease in proliferation (p = 0.003), no effects on apoptosis, and a 75% reduction in angiogenesis (p = 0.013).

CONCLUSIONS:

These studies provide the preclinical rationale for studies examining the efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type CRC.

• Authors: Jatin Roper, Michael P Richardson, Wei Vivian Wang, Larissa Georgeon Richard, Wei Chen, Erin M Coffee, Mark J Sinnamon, Lydia Lee, Peng-Chieh Chen, Roderick T Bronson, Eric S Martin, Kenneth E Hung
• Journal: PloS one (PLoS One) Vol. 6 Issue 9 Pg. e25132 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21966435 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Imidazoles
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Quinolines
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• dactolisib

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Class I Phosphatidylinositol 3-Kinases
• Colorectal Neoplasms (drug therapy, genetics, metabolism)
• HCT116 Cells
• Humans
• Imidazoles (therapeutic use)
• Immunohistochemistry
• Mice
• Mice, Knockout
• Phosphatidylinositol 3-Kinases (genetics)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (therapeutic use)
• Quinolines (therapeutic use)
• Signal Transduction (drug effects)