Dependence receptors: new targets for cancer therapy

Abstract

Dependence receptors are known to promote survival and positive signaling such as proliferation, migration, and differentiation when activated, but to actively trigger apoptosis when unbound to their ligand. Their abnormal regulation was shown to be an important feature of tumorigenesis, allowing cancer cells to escape apoptosis triggered by these receptors while promoting in parallel major aspects of tumorigenesis such as proliferation, angiogenesis, invasiveness, and chemoresistance. This involvement in multiple cancer hallmarks has raised interest in dependence receptors as targets for cancer therapy. Although additional studies remain necessary to fully understand the complexity of signaling pathways activated by these receptors and to target them efficiently, it is now clear that dependence receptors represent very exciting targets for future cancer treatment. This manuscript reviews current knowledge on the contribution of dependence receptors to cancer and highlights the potential for therapies that activate pro-apoptotic functions of these proteins.

Keywords: apoptosis; cancer hallmarks; treatment resistance; tumor progression.

Figure 1. Dependence receptor paradigm

Schematic representation of DR triggering: positive signaling in the presence (Top) and negative signaling in the absence of ligand (Bottom) (Created with BioRender.com).

Figure 2. Mechanisms of dependence receptor‐triggered apoptosis escape in cancer

Schematic representation of ways to escape DR‐triggered apoptosis: Constitutive activation of the receptor; repression of the DR apoptotic protein partner; DR loss of function; and autocrine or paracrine ligand overexpression) (Created with BioRender.com).

Figure 3. Involvement of dependence receptors in tumorigenesis and examples of drugs targeting them

Impact of Dependence Receptors on different stages of tumorigenesis. Blue boxes highlight DR effects, while red boxes highlight examples of inhibitors that target them (Created with BioRender.com).