title: Combined PI3K/mTOR and MEK inhibition provides broad antitumor activity in faithful murine cancer models.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Roberts
authors.forename: Jerry E
authors.initials: JE
authors.lastname: Usary
authors.forename: David B
authors.initials: DB
authors.lastname: Darr
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Dillon
authors.forename: Adam D
authors.initials: AD
authors.lastname: Pfefferle
authors.forename: Martin C
authors.initials: MC
authors.lastname: Whittle
authors.forename: James S
authors.initials: JS
authors.lastname: Duncan
authors.forename: Soren M
authors.initials: SM
authors.lastname: Johnson
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Combest
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johnson
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001562:Benzimidazoles / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D007093:Imidazoles; D020930:MAP Kinase Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C517975:AZD 6244; C546842:MTOR protein, human; C531198:dactolisib