title: Co-targeting cancer drug escape pathways confers clinical advantage for multi-target anticancer drugs.
abstract: Recent investigations have suggested that anticancer therapeutics may be enhanced by co-targeting the primary anticancer target and the corresponding drug escape pathways. Whether this strategy confers statistically significant clinical advantage has not been systematically investigated. This question was probed by the evaluation of the clinical status and the multiple targets of 23 approved and 136 clinical trial multi-target anticancer drugs with particular focus on those co-targeting EGFR, HER2, Abl, VEGFR2, mTOR, PI3K, Alk, MEK, KIT, and DNA topoisomerase, and some of the 14, 7, 13, 20, 6, 5, 7, 2, 4 and 10 cancer drug escape pathways respectively. Most of the approved (73.9%) and phase III (75.0%), the majority of the Phase II (62.8%) and I (53.6%), and the minority of the discontinued (35.3%) multi-target drugs were found to co-target cancer drug escape pathways. This suggests that co-targeting anticancer targets and drug escape pathways confer significant clinical advantage and such strategy can be more extensively explored.
authors.affiliation: Shenzhen Kivita Innovative Drug Discovery Center and the State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, PR China; Bioinformatics and Drug Design Group, Department of Pharmacy and Center for Computational Science and Engineering, National University of Singapore, 117543, Singapore.
authors.forename: Lin
authors.initials: L
authors.lastname: Tao
authors.affiliation: Innovative Drug Research Centre and College of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.affiliation: College of Pharmacy, State Key Laboratory of Medicinal Chemical Biology and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: Zhejiang Key Laboratory of Gastro-intestinal Pathophysiology, Zhejiang Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, No. 54 Youdian Road, Hangzhou 310006, PR China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Shenzhen Kivita Innovative Drug Discovery Center and the State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
authors.forename: Yu Yang
authors.initials: YY
authors.lastname: Jiang
authors.affiliation: Bioinformatics and Drug Design Group, Department of Pharmacy and Center for Computational Science and Engineering, National University of Singapore, 117543, Singapore. Electronic address: phacyz@nus.edu.sg.
authors.forename: Yu Zong
authors.initials: YZ
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents
keywords: Afatinib (Pubmed CID: 10184653); Anticancer; Co-target; Drug escape pathways; Erlotinib (Pubmed CID: 176870); Gefitinib (Pubmed CID: 123631); Lenvatinib (Pubmed CID: 9823820); Multi-target; Pazopanib (Pubmed CID: 10113978); Systematically; XL647 (Pubmed CID: 10458325)