title: Activation of insulin-like growth factor receptor signaling mediates resistance to histone deacetylase inhibitors.
abstract: Histone deacetylases (HDACs) are considered promising targets in the treatment of hematologic malignancies and several types of solid tumors, including non-small cell lung cancer (NSCLC). However, the efficacy of HDAC inhibitors in solid tumors is marginal, and the mechanisms underlying resistance to HDAC inhibitors are largely unknown. Here, we demonstrate the involvement of type 1 insulin-like growth factor receptor (IGF-1R) signaling in resistance to HDAC inhibitors in NSCLC. Using MTT and soft-agar colony formation assays, we selected NSCLC cell lines that exhibited intrinsic resistance to vorinostat. Treatment with vorinostat activated IGF-1R signaling in vorinostat-resistant but not vorinostat-sensitive NSCLC cells. Other HDAC inhibitors, including trichostatin A, sodium butyrate, and depsipeptide, also activated IGF-1R signaling in vorinostat-resistant NSCLC cells. Blockade of IGF-1R signaling via IGF-1R monoclonal antibodies (mAbs) or through knockdown of IGF-1R via RNA interference sensitized vorinostat-resistant cells to HDAC inhibition. Finally, IGF-1R mAbs sensitized xenograft tumors of vorinostat-resistant cells to vorinostat treatment in vivo. These findings suggest that IGF-1R activation is generally involved in resistance to HDAC inhibitors and that targeting IGF-1R is an effective strategy for overcoming resistance to HDAC inhibitors in NSCLC.
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
authors.forename: Jin-Soo
authors.initials: JS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Su-Chan
authors.initials: SC
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Min
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Kwan Hee
authors.initials: KH
authors.lastname: Park
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Seung Yeob
authors.initials: SY
authors.lastname: Hyun
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Gyungnam 621-749, Republic of Korea.
authors.forename: So Jung
authors.initials: SJ
authors.lastname: Kwon
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
authors.forename: Sun Phil
authors.initials: SP
authors.lastname: Choi
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
authors.forename: Woo-Young
authors.initials: WY
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Gyungnam 621-749, Republic of Korea.
authors.forename: Hyo-Jong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: hylee135@snu.ac.kr.
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D057890:Epigenomics; D005260:Female; D015870:Gene Expression; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D017526:Receptor, IGF Type 1
keywords: Drug resistance; Histone deacetylase inhibitor; Insulin-like growth factor receptor; Vorinostat