DRESIS: the first comprehensive landscape of drug resistance information

Abstract

Widespread drug resistance has become the key issue in global healthcare. Extensive efforts have been made to reveal not only diverse diseases experiencing drug resistance, but also the six distinct types of molecular mechanisms underlying this resistance. A database that describes a comprehensive list of diseases with drug resistance (not just cancers/infections) and all types of resistance mechanisms is now urgently needed. However, no such database has been available to date. In this study, a comprehensive database describing drug resistance information named 'DRESIS' was therefore developed. It was introduced to (i) systematically provide, for the first time, all existing types of molecular mechanisms underlying drug resistance, (ii) extensively cover the widest range of diseases among all existing databases and (iii) explicitly describe the clinically/experimentally verified resistance data for the largest number of drugs. Since drug resistance has become an ever-increasing clinical issue, DRESIS is expected to have great implications for future new drug discovery and clinical treatment optimization. It is now publicly accessible without any login requirement at: https://idrblab.org/dresis/.

Graphical Abstract

DRESIS constructed in this work systematically provides, for the first time, all six types of molecular mechanisms underlying drug resistance, covers the widest range of diseases among existing databases and describes the clinically/experimentally verified resistance data for >20 000 drugs.

Figure 1.

Schematic illustration of the six types of mechanism that are reported to play an essential role in the determination of a drug's resistance. These six mechanism types are: aberration of the drug's therapeutic target (ADTT), irregularity in drug uptake and drug efflux (IDUE), drug inactivation by structure modification (DISM), epigenetic alteration of DNA, RNA and protein (EADR), unusual activation of the pro-survival pathway (UAPP) and regulation by the disease microenvironment (RTDM). The six types of key resistance molecule (indicated using black italic font, i.e. therapeutic target, drug transporter, drug-metabolizing enzyme, epigenetics-related molecule, pathway activator/suppressor and microenvironment regulator) were considered as essential for the mechanisms of ADTT, IDUE, DISM, EADR, UAPP and RTDM, respectively. (The figure was created with Biorender.com.)

Figure 2.

Detailed descriptions on the resistance information of each drug (using doxorubicin as an example). General pharmaceutical data are provided in the upper section, which includes Drug Name, Drug Synonyms, Disease Indications (together with the corresponding Clinical Status of the drug), Drug Structures (downloadable in both 2D and 3D formats), Drug Target and External Linkage to other molecular biological databases. The resistance information of the studied drug is illustrated in the lower section, which describes a list of diseases with reported resistance for the drug. For a drug, multiple diseases were usually found with reported resistances, and the diseases were classified here according to their types of resistance evidence (clinically reported, validated by an in vivo model or identified using a cell line experiment).

Figure 3.

Illustrating the multiple types of resistance mechanisms for the drug doxorubicin using an interactive diagram. The drug is placed in the middle and surrounded by various types of mechanisms (as illustrated on the top of this diagram). Various disease classes were linked to each mechanism type, which were further connected to key resistance molecules (illustrated in outermost leaves). Doxorubicin has six types of resistance mechanisms shown by various colors in the interactive diagram. Resistance diseases are shown under each mechanism, and key resistance molecules are given for the corresponding disease. A comprehensive illustration of resistance mechanisms and resistance diseases is provided for each drug, which can be interactively accessed online.

Figure 4.

Detailed resistance mechanisms of drug that were categorized according to the disease classes. Under a mechanism type for a specific disease, the data of key resistance molecules, type of resistance evidence and experimental details are systematically shown in a typical drug page. For key resistance molecules, their alterations in resistance disease are described, and different types of resistance evidence (clinically reported, validated by an in vivo model or identified by a cell line experiment) were discovered. Various experimental details were described, which included: diverse experimental techniques, hundreds of disease cell lines and infectious strains, hundreds of in vivo models and a variety of signaling pathways regulated in the resistance diseases.

Figure 5.

A panorama diagram of resistant drugs for the disease breast cancer in DRESIS. A full list of resistant drugs is provided using the drug IDs on the vertical axis, and another list of key resistance molecules is shown by the molecule IDs on the horizontal axis. Due to the huge amount of both drugs and key molecules involved in breast cancer (also in many other diseases), DRESIS enabled the visualization of the entire panorama through dragging the sliders on both the bottom and right sides of the interactive diagram. Different types of resistance mechanisms are indicated in this diagram using circles (with the letter ‘R’ in the middle) of different colors. By placing the mouse on any of the circles, the detailed information on mechanism type, resistant drug and key molecule can be interactively viewed. This panorama diagram is valuable for the audience to have a quick and global understanding of the resistance profile for any disease of research interest.

Figure 6.

Detailed resistance mechanisms of disease that were categorized according to the drug names. Under each mechanism type for specific drugs, the data of key resistance molecules, type of resistance evidence and experimental details are systematically shown in a typical disease page. For key resistance molecules, their alterations in resistance disease were described, and different types of resistance evidence (clinically reported, validated by an in vivo model or identified by a cell line experiment) were discovered. Various experimental details are described, which included: diverse experimental techniques, hundreds of disease cell lines and infectious strains, hundreds of in vivo models and a variety of signaling pathways regulated in the resistance diseases.

Figure 7.

A typical page in DRESIS that provides the disease-specific expression abundances of the key resistance molecules. The violin plot in the upper part of this diagram shows the disease-specific abundances of a key molecule, and the abundance profiles of a total of 63 disease classes are provided for each key resistance molecule. The abundance variation, Z-score and fold change between groups are described. Red group, key molecules expressed in disease tissue of patients; green group, key molecule expressed in normal tissue of healthy individuals.

Figure 8.

A typical page in DRESIS that provides the tissue-specific expression abundances for key resistance molecules, which was drawn to describe the tissue-specific abundance variations of the key resistance molecules among different tissues. The corresponding expression data were retrieved from two benchmarks previously published in two reputable studies (105,106).