Natural Product Target Network Reveals Potential for Cancer Combination Therapies.

Steven R Chamberlin,Shannon Mcweeney,Guanming Wu,Molly Kulesz-Martin,Aurora Blucher,Lynne Shinto,Gabrielle Choonoo

doi:10.3389/fphar.2019.00557

Abstract

A body of research demonstrates examples of in vitro and in vivo synergy between natural products and anti-neoplastic drugs for some cancers. However, the underlying biological mechanisms are still elusive. To better understand biological entities targeted by natural products and therefore provide rational evidence for future novel combination therapies for cancer treatment, we assess the targetable space of natural products using public domain compound-target information. When considering pathways from the Reactome database targeted by natural products, we found an increase in coverage of 61% (725 pathways), relative to pathways covered by FDA approved cancer drugs collected in the Cancer Targetome, a resource for evidence-based drug-target interactions. Not only is the coverage of pathways targeted by compounds increased when we include natural products, but coverage of targets within those pathways is also increased. Furthermore, we examined the distribution of cancer driver genes across pathways to assess relevance of natural products to critical cancer therapeutic space. We found 24 pathways enriched for cancer drivers that had no available cancer drug interactions at a potentially clinically relevant binding affinity threshold of < 100nM that had at least one natural product interaction at that same binding threshold. Assessment of network context highlighted the fact that natural products show target family groupings both distinct from and in common with cancer drugs, strengthening the complementary potential for natural products in the cancer therapeutic space. In conclusion, our study provides a foundation for developing novel cancer treatment with the combination of drugs and natural products.

Highlights

While treatment for cancer has seen great strides in recent decades, we still face many open challenges in cancer therapy
Our final set of natural products, compiled from TarNet and TCMID, contained 50,109 compounds, uniquely identified by the five keys found in the source databases: chemical name, simplified molecular-input line-entry system (SMILES), INCHIKEY, Pubchem Compound ID and Chemical Abstracts Service (CAS) number
Most of the Network products (NPs)-target interactions were classified as Evidence Level I (94%), and most Cancer Targetome (CT) interactions were classified as Evidence Level III (95%), the absolute counts of interactions were much larger for NPs given the overall number of NPs (Figure 2A)

Summary

Introduction

While treatment for cancer has seen great strides in recent decades, we still face many open challenges in cancer therapy. Natural Product Target Network products (NPs) will increase the number of potentially therapeutically accessible targets and lead to novel combination therapies for cancer treatment. To investigate this premise, we will quantify these new therapeutic targets and associated molecular pathways, and assess the functional qualities and complementarity with FDA-approved cancer drugs of this space by using a variety of network methods. While some of the early targeted therapies have resulted in dramatic clinical responses, drug resistance often develops after an initial positive response This adaptation to treatment is known as acquired drug resistance, as opposed to intrinsic resistance, which exists prior to any cancer therapy (Holohan et al, 2013)

Methods

Results

Conclusion