title: Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer.
abstract: PI3K inhibition in combination with other agents has not been studied in the context of PIK3CA wild-type, KRAS mutant cancer. In a screen of phospho-kinases, PI3K inhibition of KRAS mutant colorectal cancer cells activated the MAPK pathway. Combination PI3K/MEK inhibition with NVP-BKM120 and PD-0325901 induced tumor regression in a mouse model of PIK3CA wild-type, KRAS mutant colorectal cancer, which was mediated by inhibition of mTORC1, inhibition of MCL-1, and activation of BIM. These findings implicate mitochondrial-dependent apoptotic mechanisms as determinants for the efficacy of PI3K/MEK inhibition in the treatment of PIK3CA wild-type, KRAS mutant cancer.
authors.affiliation: Tufts Medical Center, Division of Gastroenterology, Department of Medicine, Boston, MA, United States; Tufts Medical Center, Molecular Oncology Research Institute, Boston, MA, United States. Electronic address: jroper@tuftsmedicalcenter.org.
authors.forename: Jatin
authors.initials: J
authors.lastname: Roper
authors.affiliation: Massachusetts General Hospital, Center for Systems Biology, Boston, MA, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Sinnamon
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA, United States.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Coffee
authors.affiliation: Celgene, Discovery, Oncology Research, San Diego, CA, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Belmont
authors.affiliation: Tufts Medical Center, Molecular Oncology Research Institute, Boston, MA, United States.
authors.forename: Lily
authors.initials: L
authors.lastname: Keung
authors.affiliation: Tufts Medical Center, Division of Gastroenterology, Department of Medicine, Boston, MA, United States.
authors.forename: Larissa
authors.initials: L
authors.lastname: Georgeon-Richard
authors.affiliation: Tufts Medical Center, Division of Gastroenterology, Department of Medicine, Boston, MA, United States.
authors.forename: Wei Vivian
authors.initials: WV
authors.lastname: Wang
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA, United States.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Faber
authors.affiliation: Weill Cornell Medical College and New York-Presbyterian Hospital, Department of Medicine, New York, NY, United States.
authors.forename: Jihye
authors.initials: J
authors.lastname: Yun
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States.
authors.forename: Ömer H
authors.initials: ÖH
authors.lastname: Yilmaz
authors.affiliation: Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Martin
authors.affiliation: Tufts Medical Center, Molecular Oncology Research Institute, Boston, MA, United States.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Tsichlis
authors.affiliation: Pfizer Biotherapeutics Clinical Research, Cambridge, MA, United States.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Hung
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011905:Genes, ras; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors; D020930:MAP Kinase Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C546639:Pik3ca protein, mouse
keywords: Colorectal cancer; KRAS; MEK; Mouse model of cancer; PI3K