A highly annotated database of genes associated with platinum resistance in cancer

Abstract

Platinum-based chemotherapy, including cisplatin, carboplatin, and oxaliplatin, is prescribed to 10-20% of all cancer patients. Unfortunately, platinum resistance develops in a significant number of patients and is a determinant of clinical outcome. Extensive research has been conducted to understand and overcome platinum resistance, and mechanisms of resistance can be categorized into several broad biological processes, including (1) regulation of drug entry, exit, accumulation, sequestration, and detoxification, (2) enhanced repair and tolerance of platinum-induced DNA damage, (3) alterations in cell survival pathways, (4) alterations in pleiotropic processes and pathways, and (5) changes in the tumor microenvironment. As a resource to the cancer research community, we provide a comprehensive overview accompanied by a manually curated database of the >900 genes/proteins that have been associated with platinum resistance over the last 30 years of literature. The database is annotated with possible pathways through which the curated genes are related to platinum resistance, types of evidence, and hyperlinks to literature sources. The searchable, downloadable database is available online at http://ptrc-ddr.cptac-data-view.org .

Fig. 1. Platinum mechanism of action.

Platinum cytotoxicity is mainly caused by formation of (A) DNA adducts and (B) intra- or (C) inter-strand crosslinks. The adducts and crosslinks inhibit DNA duplication leading to a DNA damage response and eventual cell death.

Fig. 2. Mechanisms of platinum resistance.

Tumors employ multiple mechanisms to resist platinum-induced cell death. These mechanisms can be categorized as following: (1) Reduced importation and increased exportation, sequestration, and detoxification of platinum (Pt); (2) Enhanced repair and tolerance of platinum induced DNA damage and blockage of cell cycle inhibition; (3) Inhibition of apoptotic signaling, downregulation of reactive oxygen species (ROS), and increased autophagy; (4) Hypoxia and other stress responses (e.g. ER stress response); (5) Metabolic reprogramming; (6) Upregulation of key signaling pathways promoting resistance; and (7) Extracellular mechanisms that alter the extracellular matrix (ECM) and enhance tumor-promoting inflammation.

Fig. 3. Pathway annotation of genes.

A Number of genes (in Supplementary Table S1) at each level of evidence assigned to each putative platinum resistance mechanism pathway. Genes are assigned evidence scores based on experiments from cell lines, xenograft models, and/or human cancer tissue. Only pathways with at least five genes are shown. B Top GO biological process term enrichment of genes in Supplementary Table S1.