Discoidin domain receptors orchestrate cancer progression: A focus on cancer therapies

Abstract

Discoidin domain receptors (DDR), including DDR1 and DDR2, are special types of the transmembrane receptor tyrosine kinase superfamily. DDR are activated by binding to the triple-helical collagen and, in turn, DDR can activate signal transduction pathways that regulate cell-collagen interactions involved in multiple physiological and pathological processes such as cell proliferation, migration, apoptosis, and cytokine secretion. Recently, DDR have been found to contribute to various diseases, including cancer. In addition, aberrant expressions of DDR have been reported in various human cancers, which indicates that DDR1 and DDR2 could be new targets for cancer treatment. Considerable effort has been made to design DDR inhibitors and several molecules have shown therapeutic effects in pre-clinical models. In this article, we review the recent literature on the role of DDR in cancer progression, the development status of DDR inhibitors, and the clinical potential of targeting DDR in cancer therapies.

Keywords: antagonists and inhibitors; discoidin domain receptors; neoplasms; receptor protein-tyrosine kinases; therapeutic uses.

FIGURE 1

Structures and subtypes of DDR1 and DDR2. DDR1a, b, and c are kinase‐active, while DDR1d and e are kinase domain‐deficient. AA, amino acid; DS, discoidin domain; DS‐like, discoidin‐like domain; EJXM, extracellular juxtamembrane region; IJXM, intracellular juxtamembrane region; KD, kinase domain; TM, transmembrane segment

FIGURE 2

Regulatory mechanisms of DDR1/DDR2 in biological development, immunomodulation, cancer cell proliferation, invasion/migration and epithelial to mesenchymal transition