Co-targeting cancer drug escape pathways confers clinical advantage for multi-target anticancer drugs
1Shenzhen 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.
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.
Insights
Co-targeting primary cancer targets and drug escape pathways significantly improves anticancer therapeutics. This strategy, involving multiple drug targets, shows a clear clinical advantage and warrants further exploration in cancer drug development.
Area of Science:
- Oncology
- Pharmacology
- Drug Development
Background:
- Anticancer therapeutics may be enhanced by co-targeting primary cancer targets and drug escape pathways.
- The clinical advantage of this strategy has not been systematically investigated.
Purpose of the Study:
- To systematically investigate whether co-targeting primary anticancer targets and drug escape pathways confers a statistically significant clinical advantage.
Main Methods:
- Evaluation of the clinical status and multiple targets of 23 approved and 136 clinical trial multi-target anticancer drugs.
- Focus on drugs co-targeting key pathways: EGFR, HER2, Abl, VEGFR2, mTOR, PI3K, Alk, MEK, KIT, and DNA topoisomerase.
Main Results:
- Most approved (73.9%) and Phase III (75.0%) multi-target drugs co-target cancer drug escape pathways.
- A majority of Phase II (62.8%) and Phase I (53.6%) drugs also employ this strategy.
- A minority of discontinued drugs (35.3%) utilized this approach.
Conclusions:
- Co-targeting anticancer targets and drug escape pathways confers significant clinical advantage.
- This strategy can be more extensively explored for enhanced anticancer therapeutics.
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