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

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

doi:10.1016/j.phrs.2015.09.019

Cited by 52 publications

(37 citation statements)

References 69 publications

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“…The DEMs associated with each of the seven kinase targets (Supporting Information Table S2) were from the literatures (Tao et al, ) by the criterion that, in in‐vitro and in‐vivo studies of the drug‐targeted cancers, each DEM actively hinders target inhibition by the drug, or the resistance against the targeted‐drugs can be significantly reduced by modulating the DEM, or the co‐targeting of the target and each DEM by a drug combination synergistically inhibit the target and/or enhance the anticancer activity with respect to the individual targeted‐drug (Karamouzis et al, ; Ng et al, ; Poulikakos & Solit, ; Sawyers, ).…”

Section: Methodsmentioning

confidence: 99%

“…counteractive feedback loops that evade the drug modulation of a target (Avril et al, 2017;Boshuizen et al, 2018;Tao et al, 2015). These drug-escape actions can be overcome by co-inhibiting the targetassociated DEMs (Dienstmann, De Dosso, Felip, & Tabernero, 2012;Kanda et al, 2013;Karamouzis, Konstantinopoulos, & Papavassiliou, 2009;Ng et al, 2012;Poulikakos & Solit, 2011;Sawyers, 2007) using multi-target drugs (Katakami et al, 2013;Schlumberger et al, 2015) and drug combinations (Qi et al, 2011).…”

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confidence: 99%

“…These drug-escape actions can be overcome by co-inhibiting the targetassociated DEMs (Dienstmann, De Dosso, Felip, & Tabernero, 2012;Kanda et al, 2013;Karamouzis, Konstantinopoulos, & Papavassiliou, 2009;Ng et al, 2012;Poulikakos & Solit, 2011;Sawyers, 2007) using multi-target drugs (Katakami et al, 2013;Schlumberger et al, 2015) and drug combinations (Qi et al, 2011). The clinical advantage of coinhibiting DEMs has been indicated by the count of the DEM cotargeted drugs among all the multi-target anticancer drugs in clinics and clinical trials, with the majority (73.9-75.0%) of the approved and phase III drugs and the minority (53.6-62.8%) of phase I and II drugs co-inhibiting at least one target-associated DEM (Tao et al, 2015).…”

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confidence: 99%

“…The drug-escape mediator inhibitory and sales profiles of the FDA-approved multi-target kinase inhibitor drugs grouped into drug sales comparison (DSC) groups drugs, are two Abl-DSC groups for chronic myelogenous leukemia, two EGFR-DSC groups and one Alk-DSC group for non-small cell lung cancer, two VEGFR2-DSC and one mTOR-DSC group for renal cell carcinoma, one VEGFR2-DSC group for thyroid cancer, and one BRaf-DSC and one Mek-DSC group for melanoma. The remaining one drug, the Abl inhibitor imatinib, cannot be grouped into any Abl-DSC group because Imatinib has been approved 5-11 years earlier than the other Abl inhibitors.2.4 | Search of DEMs associated with the efficacy targets of drugsThe DEMs associated with each of the seven kinase targets (SupportingInformation Table S2) were from the literatures(Tao et al, 2015) by the criterion that, in in-vitro and in-vivo studies of the drug-targeted cancers, each DEM actively hinders target inhibition by the drug, or the resistance against the targeted-drugs can be significantly reduced by modulating the DEM, or the co-targeting of the target and each DEM by a drug combination synergistically inhibit the target and/or enhance the anticancer activity with respect to the indi-For the majority (68%) of the 25 drugs, we were able to find the literature-reported experimental potency data of at least one kinase DEMs, but none of these drugs were found to show sufficient inhibitory potency to any non-kinase DEMs. Hence, there appears to be a need for additional experimental studies to probe the potential activities of these drugs against the non-kinase DEMs.2.6 | Human plasma free drug concentration and the criterion for the effective inhibition of drug target and associated DEMs under clinical conditions…”

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confidence: 99%

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Drug sales confirm clinical advantage of multi‐target inhibition of drug escapes by anticancer kinase inhibitors

Chen¹,

Yang

Chen

et al. 2018

Drug Development Research

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The clinical advantage of co‐targeting cancer drug escape has been indicated by the percentage of these co‐targeting drugs among all multi‐target drugs in clinics and clinical trials. This clinical advantage needs to be further interrogated from such perspectives as the clinical impact of multi‐target inhibition of drug‐escape mediators. This impact may be reflected by drug sales data, that is, multi‐target inhibition of higher number of drug‐escape mediators favors the expanded coverage of drug‐resistant patients leading to higher sales. We investigated whether this expectation is followed by the 25 FDA‐approved anticancer kinase inhibitors, which were divided into 11 groups of comparable therapeutic mechanisms and approval years. We found 19 (76%) drugs to follow and 3 (12%) drugs not to follow this expectation. The remaining two (8%) and one (4%) drugs cannot be assessed due to insufficient data and incomparability. Therefore, drug sales strongly indicate the clinical advantage of multi‐target inhibition of cancer drug escapes.

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Section: Methodsmentioning

confidence: 99%

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Drug sales confirm clinical advantage of multi‐target inhibition of drug escapes by anticancer kinase inhibitors

Chen¹,

Yang

Chen

et al. 2018

Drug Development Research

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“…In the meantime, the approved combination products targeting the human kinome produce synergistic effects triggered by actions converging at a specific pathway site, which enhances its clinical capacity for treating diseases of great complexity [10,21,22]. So far, several studies have been conducted to assess the applicability domain of both multi-target drug and combination product and to analyze their advantages over another [23,24].…”

Section: Introductionmentioning

confidence: 99%

The Human Kinome Targeted by FDA Approved Multi-Target Drugs and Combination Products: A Comparative Study from the Drug-Target Interaction Network Perspective

Wang

et al. 2016

PLoS ONE

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The human kinome is one of the most productive classes of drug target, and there is emerging necessity for treating complex diseases by means of polypharmacology (multi-target drugs and combination products). However, the advantages of the multi-target drugs and the combination products are still under debate. A comparative analysis between FDA approved multi-target drugs and combination products, targeting the human kinome, was conducted by mapping targets onto the phylogenetic tree of the human kinome. The approach of network medicine illustrating the drug-target interactions was applied to identify popular targets of multi-target drugs and combination products. As identified, the multi-target drugs tended to inhibit target pairs in the human kinome, especially the receptor tyrosine kinase family, while the combination products were able to against targets of distant homology relationship. This finding asked for choosing the combination products as a better solution for designing drugs aiming at targets of distant homology relationship. Moreover, sub-networks of drug-target interactions in specific disease were generated, and mechanisms shared by multi-target drugs and combination products were identified. In conclusion, this study performed an analysis between approved multi-target drugs and combination products against the human kinome, which could assist the discovery of next generation polypharmacology.

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Screening and identification of Caulis Sinomenii bioactive ingredients with dual‐target NF‐κB inhibition and β_2‐AR agonizing activities

Sun

Han

Wang

et al. 2016

Biomedical Chromatography

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Caulis Sinomenii (CS) is a valuable traditional medicine in China. Its extract can act as an anti-inflammatory agent and a vascular smooth muscle relaxant. However, the underlying mechanisms remain unknown. In this study, we developed a simple dual-target method based on ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry combined with a dual-target bioactive screening assay for anti-inflammatory and antispasmodic activities to characterize the chemical structure of various bioactive compounds of CS rapidly. Seven potential NF-κB inhibitors were identified, including laudanosoline-1-O-xylopyranose, 6-O-methyl-laudanosoline-1-O-glucopyranoside, menisperine, sinomenine, laurifoline, magnoflorine and norsinoacutin. Furthermore, IL-6 and IL-8 assays confirmed the anti-inflammatory effects of these potential NF-κB inhibitors, in which laudanosoline-1-O-d-xylopyranose and menisperine were revealed as novel NF-κB inhibitors. Among the seven identified alkaloids, three potential β -adrenergic receptor agonists, including sinomenine, magnoflorine and laurifoline, were characterized using a luciferase reporter system to measure for the activity of β -adrenergic receptor agonists. Finally, sinomenine, magnoflorine and laurifoline were identified not only as potential NF-κB inhibitors but also as potential β -adrenegic receptor agonists, which is the first time this has been reported. Molecular dynamic simulation and docking results suggest that the three dual-bioactive constituents could not only inhibit Pseudomonas aeruginosa PAK strain-induced inflammatory responses via a negative regulation of the Braf protein that participates in MAPK signaling pathway but also activate the β -adrenegic receptor. These results suggest that CS extract has dual signaling activities with potential clinical application as a novel drug for asthma.

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

Cited by 52 publications

References 69 publications

Drug sales confirm clinical advantage of multi‐target inhibition of drug escapes by anticancer kinase inhibitors

Drug sales confirm clinical advantage of multi‐target inhibition of drug escapes by anticancer kinase inhibitors

The Human Kinome Targeted by FDA Approved Multi-Target Drugs and Combination Products: A Comparative Study from the Drug-Target Interaction Network Perspective

Screening and identification of Caulis Sinomenii bioactive ingredients with dual‐target NF‐κB inhibition and β_2‐AR agonizing activities

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

Cited by 52 publications

References 69 publications

Drug sales confirm clinical advantage of multi‐target inhibition of drug escapes by anticancer kinase inhibitors

Drug sales confirm clinical advantage of multi‐target inhibition of drug escapes by anticancer kinase inhibitors

The Human Kinome Targeted by FDA Approved Multi-Target Drugs and Combination Products: A Comparative Study from the Drug-Target Interaction Network Perspective

Screening and identification of Caulis Sinomenii bioactive ingredients with dual‐target NF‐κB inhibition and β2‐AR agonizing activities

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Product

Resources

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Screening and identification of Caulis Sinomenii bioactive ingredients with dual‐target NF‐κB inhibition and β_2‐AR agonizing activities