title: Inhibition of the growth of patient-derived pancreatic cancer xenografts with the MEK inhibitor trametinib is augmented by combined treatment with the epidermal growth factor receptor/HER2 inhibitor lapatinib.
abstract: Mutations of the oncogene KRAS are important drivers of pancreatic cancer progression. Activation of epidermal growth factor receptor (EGFR) and human EGFR2 (HER2) is observed frequent in pancreatic adenocarcinomas. Because of co-activation of these two signaling pathways, we assessed the efficacy of inhibition of EGFR/HER2 receptors and the downstream KRAS effector, mitogen-activated protein kinase/extracellular-signal regulated kinase (ERK) kinase 1 and 2 (MEK1/2), on pancreatic cancer proliferation in vitro and in a murine orthotopic xenograft model. Treatment of established and patient-derived pancreatic cancer cell lines with the MEK1/2 inhibitor trametinib (GSK1120212) inhibited proliferation, and addition of the EGFR/HER2 inhibitor lapatinib enhanced the inhibition elicited by trametinib in three of eight cell lines. Importantly, in the orthotopic xenograft model, treatment with lapatinib and trametinib resulted in significantly enhanced inhibition of tumor growth relative to trametinib treatment alone in four of five patient-derived tumors tested and was, in all cases, significantly more effective in reducing the size of established tumors than treatment with lapatinib or trametinib alone. Acute treatment of established tumors with trametinib resulted in an increase in AKT2 phosphorylation that was blunted in mice treated with both trametinib and lapatinib. These data indicate that inhibition of the EGFR family receptor signaling may contribute to the effectiveness of MEK1/2 inhibition of tumor growth possibly through the inhibition of feedback activation of receptor tyrosine kinases in response to inhibition of the RAS-RAF-MEK-ERK pathway. These studies provide a rationale for assessing the co-inhibition of these pathways in the treatment of pancreatic cancer patients.
authors: Department of Surgery, University of Virginia Health System, Charlottesville, VA, USA.
authors: Dustin M
authors: DM
authors: Walters
authors: James M
authors: JM
authors: Lindberg
authors: Sara J
authors: SJ
authors: Adair
authors: Timothy E
authors: TE
authors: Newhook
authors: Catharine R
authors: CR
authors: Cowan
authors: Jayme B
authors: JB
authors: Stokes
authors: Cheryl A
authors: CA
authors: Borgman
authors: Edward B
authors: EB
authors: Stelow
authors: Bryce T
authors: BT
authors: Lowrey
authors: Maria E
authors: ME
authors: Chopivsky
authors: Tona M
authors: TM
authors: Gilmer
authors: John T
authors: JT
authors: Parsons
authors: Todd W
authors: TW
authors: Bauer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D000077341:Lapatinib; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011728:Pyridones / Q000008:administration & dosage*; D011744:Pyrimidinones / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077341:Lapatinib; D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C560077:trametinib