title: Targeting AKT with the allosteric AKT inhibitor MK-2206 in non-small cell lung cancer cells with acquired resistance to cetuximab.
abstract: The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for use in oncology. Despite clinical success the majority of patients do not respond to cetuximab and those who initially respond frequently acquire resistance. To understand how tumor cells acquire resistance to cetuximab we developed a model of resistance using the non-small cell lung cancer line NCI-H226. We found that cetuximab-resistant (Ctx (R) ) clones manifested strong activation of EGFR, PI3K/AKT and MAPK. To investigate the role of AKT signaling in cetuximab resistance we analyzed the activation of the AKT pathway effector molecules using a human AKT phospho-antibody array. Strong activation was observed in Ctx (R) clones for several key AKT substrates including c-jun, GSK3β, eIF4E, rpS6, IKKα, IRS-1 and Raf1. Inhibition of AKT signaling by siAKT1/2 or by the allosteric AKT inhibitor MK-2206 resulted in robust inhibition of cell proliferation in all Ctx (R) clones. Moreover, the combinational treatment of cetuximab and MK-2206 resulted in further decreases in proliferation than either drug alone. This combinatorial treatment resulted in decreased activity of both AKT and MAPK thus highlighting the importance of simultaneous pathway inhibition to maximally affect the growth of Ctx (R) cells. Collectively, our findings demonstrate that AKT activation is an important pathway in acquired resistance to cetuximab and suggests that combinatorial therapy directed at both the AKT and EGFR/MAPK pathways may be beneficial in this setting.
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Wisconsin Institute for Medical Research, Madison, WI, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Iida
authors.forename: Toni M
authors.initials: TM
authors.lastname: Brand
authors.forename: David A
authors.initials: DA
authors.lastname: Campbell
authors.forename: Megan M
authors.initials: MM
authors.lastname: Starr
authors.forename: Neha
authors.initials: N
authors.lastname: Luthar
authors.forename: Anne M
authors.initials: AM
authors.lastname: Traynor
authors.forename: Deric L
authors.initials: DL
authors.lastname: Wheeler
mesh_terms: D000494:Allosteric Regulation; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D000068818:Cetuximab
keywords: AKT; EGFR; MAPK; MK-2206; acquired cetuximab-resistance; cetuximab; non-small cell lung cancer