title: The HSP90 inhibitor, NVP-AUY922, sensitizes KRAS-mutant non-small cell lung cancer with intrinsic resistance to MEK inhibitor, trametinib.
abstract: RAS-driven tumors are often difficult to treat with conventional therapies and therefore, novel treatment strategies are necessary. The present study describes a promising targeted therapeutic strategy against non-small cell lung cancer (NSCLC) harboring KRAS mutations, which has intrinsic resistance to MEK inhibition. Results showed that intrinsic resistance to MEK inhibition occurred via high AKT expression by PI3K activation as a bypass pathway. The HSP90 inhibitor AUY922 suppressed PI3K-AKT-mTOR and RAF-MEK-ERK, and rendered cells sensitive to trametinib (GSK1120212). Synergy from the combination of the two drugs was observed in only sub-therapeutic concentrations of either drug. Dual inhibition of the HSP90 and MEK signaling pathways with sub-therapeutic doses may represent a potent therapeutic strategy to treat KRAS-mutant NSCLC with intrinsic resistance to MEK inhibition and to resolve the toxicity observed upon dual inhibition of AKT and MEK at therapeutic doses in clinical trials.
authors.affiliation: Institute for Innovative Cancer Research, College of Medicine, Asan Medical Center, University of Ulsan, Seoul 138-736, Republic of Korea.
authors.forename: Kang-Seo
authors.initials: KS
authors.lastname: Park
authors.affiliation: Department of Oncology, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Bora
authors.initials: B
authors.lastname: Oh
authors.affiliation: Department of Oncology, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Mi-Hee
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Institute for Innovative Cancer Research, College of Medicine, Asan Medical Center, University of Ulsan, Seoul 138-736, Republic of Korea.
authors.forename: Ky-Youb
authors.initials: KY
authors.lastname: Nam
authors.affiliation: Institute for Innovative Cancer Research, College of Medicine, Asan Medical Center, University of Ulsan, Seoul 138-736, Republic of Korea.
authors.forename: Hae Ran
authors.initials: HR
authors.lastname: Jin
authors.affiliation: Department of Oncology, Asan Medical Center, Seoul, Republic of Korea; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
authors.forename: Hannah
authors.initials: H
authors.lastname: Yang
authors.affiliation: Institute for Innovative Cancer Research, College of Medicine, Asan Medical Center, University of Ulsan, Seoul 138-736, Republic of Korea.
authors.forename: Junyoung
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Oncology, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Sang-We
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Institute for Innovative Cancer Research, College of Medicine, Asan Medical Center, University of Ulsan, Seoul 138-736, Republic of Korea; Department of Oncology, Asan Medical Center, Seoul, Republic of Korea. Electronic address: leedaeho@amc.seoul.kr.
authors.forename: Dae Ho
authors.initials: DH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D012118:Resorcinols / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D012118:Resorcinols; C560077:trametinib; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Combination therapy; HSP90 inhibitor; KRAS mutation; MEK inhibitor; NSCLC