title: Synergistic effects of concurrent blockade of PI3K and MEK pathways in pancreatic cancer preclinical models.
abstract: Patients with pancreatic cancer have dismal prognoses, and novel therapies are urgently needed. Mutations of the KRAS oncogene occur frequently in pancreatic cancer and represent an attractive target. Direct targeting of the predominant KRAS pathways have been challenging and research into therapeutic strategies have been now refocused on pathways downstream of KRAS, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK [MEK]). We hypothesized that concurrent inhibition of the PI3K and MEK pathways would result in synergistic antitumor activity, as it would circumvent the compensatory feedback loop between the two pathways. We investigated the combined effect of the PI3K inhibitor, GDC0941, and the MEK inhibitor, AZD6244, on cell viability, apoptosis and cell signaling in a panel of pancreatic cancer cell lines. An in vivo analysis was conducted on pancreatic cancer xenografts. While BxPC-3 (KRAS wild type) and MIA PaCa-2 (KRAS mutated) cell lines were sensitive to GDC0941 and AZD6244 as single agents, synergistic inhibition of tumor cell growth and induction of apoptosis were observed in both cell lines when the two drugs were combined. Interestingly, phosphorylation of the cap-dependent translational components, 4E-binding protein (p-4E-BP1) and S6 was found to be closely associated with sensitivity to GDC0941 and AZD6244. In BxPC-3 cell xenografts, survival differences were observed between the control and the AZD6244, GDC0941, and combination groups. Our study provides the rationale for concurrent targeting of the PI3K and MEK pathways, regardless of KRAS status, and suggests that phosphorylation of 4E-BP1and S6 can serve as a predictive biomarker for response to treatment.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhong
authors.forename: Cesar
authors.initials: C
authors.lastname: Sanchez
authors.forename: Dirk
authors.initials: D
authors.lastname: Spitzer
authors.forename: Dirk
authors.initials: D
authors.lastname: Spitrzer
authors.forename: Stacy
authors.initials: S
authors.lastname: Plambeck-Suess
authors.forename: Jesse
authors.initials: J
authors.lastname: Gibbs
authors.forename: Williams G
authors.initials: WG
authors.lastname: Hawkins
authors.forename: David
authors.initials: D
authors.lastname: Denardo
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Robert A
authors.initials: RA
authors.lastname: Pufahl
authors.forename: Albert C
authors.initials: AC
authors.lastname: Lockhart
authors.forename: Mai
authors.initials: M
authors.lastname: Xu
authors.forename: David
authors.initials: D
authors.lastname: Linehan
authors.forename: Jason
authors.initials: J
authors.lastname: Weber
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors