title: Co-treatment with panitumumab and trastuzumab augments response to the MEK inhibitor trametinib in a patient-derived xenograft model of pancreatic cancer.
abstract: Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and epidermal growth factor receptor (EGFR) family signaling are drivers of tumorigenesis in pancreatic ductal adenocarcinoma (PDAC). Previous studies have demonstrated that combinatorial treatment of PDAC xenografts with the mitogen-activated protein kinase-extracellular-signal-regulated kinase (ERK) kinase1/2 (MEK1/2) inhibitor trametinib and the dual EGFR/human epidermal growth factor receptor 2 (HER2) inhibitor lapatinib provided more effective inhibition than either treatment alone. In this study, we have used the therapeutic antibodies, panitumumab (specific for EGFR) and trastuzumab (specific for HER2), to probe the role of EGFR and HER2 signaling in the proliferation of patient-derived xenograft (PDX) tumors. We show that dual anti-EGFR and anti-HER2 therapy significantly augmented the growth inhibitory effects of the MEK1/2 inhibitor trametinib in three different PDX tumors. While significant growth inhibition was observed in both KRAS mutant xenograft groups receiving trametinib and dual antibody therapy (tumors 366 and 608), tumor regression was observed in the KRAS wild-type xenografts (tumor 738) treated in the same manner. Dual antibody therapy in conjunction with trametinib was equally or more effective at inhibiting tumor growth and with lower apparent toxicity than trametinib plus lapatinib. Together, these studies provide further support for a role for EGFR and HER2 in pancreatic cancer proliferation and underscore the importance of therapeutic intervention in both the KRAS-rapidly accelerated fibrosarcoma kinase (RAF)-MEK-ERK and EGFR-HER2 pathways to achieve maximal therapeutic efficacy in patients.
authors.affiliation: Department of Surgery, University of Virginia Health System, Charlottesville, VA, 22908 USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Lindberg
authors.affiliation: Department of Surgery, University of Virginia Health System, Charlottesville, VA, 22908 USA.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Newhook
authors.affiliation: Department of Surgery, University of Virginia Health System, Charlottesville, VA, 22908 USA.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Adair
authors.affiliation: Department of Surgery, University of Virginia Health System, Charlottesville, VA, 22908 USA.
authors.forename: Dustin M
authors.initials: DM
authors.lastname: Walters
authors.affiliation: Department of Surgery, University of Virginia Health System, Charlottesville, VA, 22908 USA.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Kim
authors.affiliation: Department of Pathology, University of Virginia Health System, Charlottesville, VA, 22908 USA.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Stelow
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA, 22908 USA.
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Parsons
authors.affiliation: Department of Surgery, University of Virginia Health System, Charlottesville, VA, 22908 USA. Electronic address: twb7f@virginia.edu.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Bauer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077544:Panitumumab; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000068878:Trastuzumab; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D000077544:Panitumumab; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011728:Pyridones; D011744:Pyrimidinones; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C560077:trametinib