Co-targeting cancer drug escape pathways confers clinical advantage for multi-target anticancer drugs

Lin Tao; Feng Zhu; Feng Xu; Zhe Chen; Yu Yang Jiang; Yu Zong Chen

doi:10.1016/j.phrs.2015.09.019

Co-targeting cancer drug escape pathways confers clinical advantage for multi-target anticancer drugs

Pharmacol Res. 2015 Dec:102:123-31. doi: 10.1016/j.phrs.2015.09.019. Epub 2015 Oct 9.

Authors

Lin Tao¹, Feng Zhu², Feng Xu³, Zhe Chen⁴, Yu Yang Jiang⁵, Yu Zong Chen⁶

Affiliations

¹ 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.
² Innovative Drug Research Centre and College of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, PR China.
³ College of Pharmacy, State Key Laboratory of Medicinal Chemical Biology and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.
⁴ 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.
⁵ 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.
⁶ 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.

PMID: 26438971
DOI: 10.1016/j.phrs.2015.09.019

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.

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).

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Antineoplastic Agents / therapeutic use*
Clinical Trials as Topic
Drug Delivery Systems / methods
Humans
Neoplasms / drug therapy*

Substances

Antineoplastic Agents