MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo.
The serine/threonine kinase Akt lies at a critical signaling node downstream of phosphatidylinositol-3-kinase and is important in promoting cell survival and inhibiting apoptosis. An Akt inhibitor may be particularly useful for cancers in which increased Akt signaling is associated with reduced sensitivity to cytotoxic agents or receptor tyrosine kinase inhibitors. We evaluated the effect of a novel allosteric Akt inhibitor, MK-2206, in combination with several anticancer agents. In vitro, MK-2206 synergistically inhibited cell proliferation of human cancer cell lines in combination with molecular targeted agents such as erlotinib (an epidermal growth factor receptor inhibitor) or lapatinib (a dual epidermal growth factor receptor/human epidermal growth factor receptor 2 inhibitor). Complementary inhibition of erlotinib-insensitive Akt phosphorylation by MK-2206 was one mechanism of synergism, and a synergistic effect was found even in erlotinib-insensitive cell lines. MK-2206 also showed synergistic responses in combination with cytotoxic agents such as topoisomerase inhibitors (doxorubicin, camptothecin), antimetabolites (gemcitabine, 5-fluorouracil), anti-microtubule agents (docetaxel), and DNA cross-linkers (carboplatin) in lung NCI-H460 or ovarian A2780 tumor cells. The synergy with docetaxel depended on the treatment sequence; a schedule of MK-2206 dosed before docetaxel was not effective. MK-2206 suppressed the Akt phosphorylation that is induced by carboplatin and gemcitabine. In vivo, MK-2206 in combination with these agents exerted significantly more potent tumor inhibitory activities than each agent in the monotherapy setting. These findings suggest that Akt inhibition may augment the efficacy of existing cancer therapeutics; thus, MK-2206 is a promising agent to treat cancer patients who receive these cytotoxic and/or molecular targeted agents.
Hirai
Hiroshi
H
Department of Oncology, Banyu Tsukuba Research Institute, Merck Research Laboratories, Tsukuba, Ibaraki 300-2611, Japan. yrdyc661@yahoo.co.jp
Sootome
Hiroshi
H
Nakatsuru
Yoko
Y
Miyama
Katsuyoshi
K
Taguchi
Shunsuke
S
Tsujioka
Kyoko
K
Ueno
Yoko
Y
Hatch
Harold
H
Majumder
Pradip K
PK
Pan
Bo-Sheng
BS
Kotani
Hidehito
H
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002166:Camptothecin / Q000008:administration & dosage / Q000494:pharmacology; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D000077341:Lapatinib; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D011799:Quinazolines; D000077341:Lapatinib; D016190:Carboplatin; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D002166:Camptothecin