Combined PI3K/mTOR and MEK inhibition provides broad antitumor activity in faithful murine cancer models.

Abstract

PURPOSE:

Anticancer drug development is inefficient, but genetically engineered murine models (GEMM) and orthotopic, syngeneic transplants (OST) of cancer may offer advantages to in vitro and xenograft systems.

EXPERIMENTAL DESIGN:

We assessed the activity of 16 treatment regimens in a RAS-driven, Ink4a/Arf-deficient melanoma GEMM. In addition, we tested a subset of treatment regimens in three breast cancer models representing distinct breast cancer subtypes: claudin-low (T11 OST), basal-like (C3-TAg GEMM), and luminal B (MMTV-Neu GEMM).

RESULTS:

Like human RAS-mutant melanoma, the melanoma GEMM was refractory to chemotherapy and single-agent small molecule therapies. Combined treatment with AZD6244 [mitogen-activated protein-extracellular signal-regulated kinase kinase (MEK) inhibitor] and BEZ235 [dual phosphoinositide-3 kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor] was the only treatment regimen to exhibit significant antitumor activity, showed by marked tumor regression and improved survival. Given the surprising activity of the "AZD/BEZ" combination in the melanoma GEMM, we next tested this regimen in the "claudin-low" breast cancer model that shares gene expression features with melanoma. The AZD/BEZ regimen also exhibited significant activity in this model, leading us to testing in even more diverse GEMMs of basal-like and luminal breast cancer. The AZD/BEZ combination was highly active in these distinct breast cancer models, showing equal or greater efficacy compared with any other regimen tested in studies of over 700 tumor-bearing mice. This regimen even exhibited activity in lapatinib-resistant HER2(+) tumors.

CONCLUSION:

These results show the use of credentialed murine models for large-scale efficacy testing of diverse anticancer regimens and predict that combinations of PI3K/mTOR and MEK inhibitors will show antitumor activity in a wide range of human malignancies.

• Authors: Patrick J Roberts, Jerry E Usary, David B Darr, Patrick M Dillon, Adam D Pfefferle, Martin C Whittle, James S Duncan, Soren M Johnson, Austin J Combest, Jian Jin, William C Zamboni, Gary L Johnson, Charles M Perou, Norman E Sharpless
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 19 Pg. 5290-303 (Oct 01 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22872574 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AZD 6244
• Benzimidazoles
• Imidazoles
• Phosphoinositide-3 Kinase Inhibitors
• Quinolines
• MTOR protein, human
• TOR Serine-Threonine Kinases
• MAP Kinase Kinase Kinases
• dactolisib

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Benzimidazoles (administration & dosage)
• Breast Neoplasms (drug therapy)
• Female
• Humans
• Imidazoles (administration & dosage)
• MAP Kinase Kinase Kinases (antagonists & inhibitors, metabolism)
• Mammary Neoplasms, Animal (drug therapy, genetics, pathology)
• Melanoma (drug therapy, genetics, pathology)
• Mice
• Neoplasms, Experimental (drug therapy, genetics, pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Quinolines (administration & dosage)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)