title: Cotargeting MAPK and PI3K signaling with concurrent radiotherapy as a strategy for the treatment of pancreatic cancer.
abstract: There is an urgent need for the development of novel therapies to treat pancreatic cancer, which is among the most lethal of all cancers. KRAS-activating mutations, which are found in more than 90% of pancreatic adenocarcinomas, drive tumor dependency on the Ras/MAPK and Akt signaling pathways. Radiation is currently being explored as a component of the standard treatment regimen for pancreatic cancer. This study's purpose was to test the hypothesis that MAP kinase kinase (MEK or MAP2K) inhibitors will offer clear therapeutic benefit when integrated into radiotherapy treatment regimens for treatment of this disease. We explored the activation of the mitogen-activated protein kinase (MAPK) and Akt pathways in response to radiation in multiple pancreatic tumor cell lines. Small molecule inhibitors of MEK (PD0325901) and Akt (API-2) were subsequently evaluated for their radiosensitizing potential alone and in combination. In vivo efficacy was tested in subcutaneous MIA-PaCa2 xenografts. Phosphorylated levels of extracellular signal-regulated kinase (ERK)-1/2 and Akt were found to increase in response to radiation treatment in our pancreatic tumor cell line panel. MEK inhibitor-induced radiosensitization was observed in vitro and in vivo. The further addition of an Akt inhibitor to the MEK inhibitor/radiation regimen resulted in enhanced therapeutic gain as determined by increased radiosensitization and tumor cell death. In conclusion, MEK inhibition results in growth arrest, apoptosis, and radiosensitization of multiple preclinical pancreatic tumor models, and the effects can be enhanced by combination with an Akt inhibitor. These results provide rationale for further testing of a treatment regimen in pancreatic cancer that combines MEK inhibition with radiation, optimally in conjunction with Akt inhibition.
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan, USA. Terence.Williams@osumc.edu
authors.forename: Terence M
authors.initials: TM
authors.lastname: Williams
authors.forename: Athena R
authors.initials: AR
authors.lastname: Flecha
authors.forename: Paul
authors.initials: P
authors.lastname: Keller
authors.forename: Ashwin
authors.initials: A
authors.lastname: Ram
authors.forename: David
authors.initials: D
authors.lastname: Karnak
authors.forename: Stefanie
authors.initials: S
authors.lastname: Galbán
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Galbán
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
authors.forename: Judith
authors.initials: J
authors.lastname: Sebolt-Leopold
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002747:Chlorpropamide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D003131:Combined Modality Therapy; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D000096926:Benzenesulfonamides
chemical_list: D001549:Benzamides; D002747:Chlorpropamide; D004159:Diphenylamine; D004791:Enzyme Inhibitors; D020928:Mitogen-Activated Protein Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011838:Radiation-Sensitizing Agents; C111224:API 2; D000096926:Benzenesulfonamides; C506614:mirdametinib