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Oncogene Addiction As a Rationale for Targeted Anti-Cancer Therapy in Hepatocellular Carcinoma

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Oncogene Addiction As a Rationale for Targeted Anti-Cancer Therapy in Hepatocellular Carcinoma 호암상 수상 기념특강 Oncogene addiction as a rationale for targeted anti-cancer therapy in hepatocellular carcinoma Dae-Ghon Kim Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Korea Abstract The concept of oncogene addiction was first introduced by Bernard Weinstein in 2000, with particular reference to the observation that some cyclin D-overexpressing cancers reverse their malignant phenotype upon cyclin-D deple- tion by means of RNA interference. It postulates that some tumours rely on one single dominant oncogene for growth and survival, so that inhibition of this specific oncogene is sufficient to halt the neoplastic phenotype. A large amount of evidence has proven the pervasive power of this notion, both in basic research and in therapeutic applications. Application of this concept to the clinical setting has achieved variable success in some various cancer types, including chronic myelogeneous leukaemia harbouring the BCR-ABL translocation, Erb2 overexpressing breast cancer, and non-small cell lung cancer harbouring a subset of EGFR mutations (Table1). However, in the face of such a considerable body of knowledge, the intimate molecular mechanisms mediating this phenomenon remain elusive. At the clinical level, successful translation of the oncogene addiction model into the rational and effective design of targeted therapeutics against individual oncoproteins still faces major obstacles, mainly due to the emergence of escape mechanisms and drug resistance. Sorafenib, a tyrosine kinase inhibitor (TKI), has demon- strated clinical efficacy in patients with HCC. Studies in patients with lung, breast, or colorectal cancers indicated that the genetic heterogeneity of cancer cells within a tumor affect its response to therapeutics designed to target specific molecules. When tumor progression requires alterations in specific oncogenes (oncogene addiction), drugs that selectively block their products might slow tumor growth. However, no specific oncogene alterations are yet known to be implicated in HCC progression, so it is important to improve our understanding of its molecular pathogenesis. Identification of oncogenes that mediate progression of HCC, and trials that monitor their products as biomarkers, might lead to personalized therapy; reagents that interfere with signaling pathways required for HCC progression might be used to treat selected populations, and thereby maximize the efficacy and cost-benefit. References 1. Weinstein IB, Joe A. Oncogene addiction. cancer Res. 2008 ;68:3077-80. 2. Weinstein IB, Joe AK. Mechanisms of disease: oncogene addiction—a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 2006; 3: 448-57. www.kasl.org 9 제21차 대한간학회 추계학술대회 Table 1. Oncogene addiction: studies in mice, studies in human cancer cell lines, and clinical evidence Studies in mice* Targeted oncogene Cancer type c-myc T cell and acute myeloid Leukemia Bcr-Abl Leukemia H-ras Melanoma K-ras Lung c-myc Pancreatic β-cell c-myc Osteogenic sarcoma Her-2/neu Breast c-myc Breast Wnt-1 Breast Studies in human cancer cell lines† Targeted oncogene Cancer cell line Her-2 Breast Cyclin D1 Esophagus, colon, pancreatic, squamous, nasopharyngeal K-rasmut Pancreatic K-rasv12 Pancreatic β-Catenin Colon Cyclin E Liver Mutant β-Raf Melanoma MITF Melanoma Clinical evidence Targeted oncogene (s) Disease Agent‡ HER-2 Breast§,∥ Trastuzumab (combination) BCR/ABL Chronic myeloid leukemia§ Imatinib (monotherapy) C-KIT Gastrointestinal stromal tumor§ Imatinib (monotherapy) EGFR NSCLC§ Gefitinib, erlotinib§ (monotherapy) EGFR Head and neck, colorectal§ Cetuximab (combination) EGFR Pancreas§ Erlotinib (combination) VEGF Breast, colorectal§,∥, kidney Bevacizumab (combination) VEGFR, RAF Kidney§ Sorafenib (monotherapy) *Switching off the indicated oncogene led to growth inhibition, differentiation, apoptosis and/or tumor regression. †Treatment of these cell lines with an antisense oligonucleotide or a RNAi directed to the respective oncogene caused growth inhibition, and in some cases, decreased tumorigenicity and increased chemosensitivity. ‡Treatment regimen indicates agent alone (monotherapy) or in combination with cytotoxic agents (combination). §Food and Drug Administration–approved. ∥Phase III evidence shows improved disease-free or overall survival rates. 10 대한간학회.
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