Targeting BCL2-Proteins for the Treatment of Solid Tumours

Abstract

Due to their central role in the regulation of apoptosis, the antiapoptotic BCL2-proteins are highly promising targets for the development of novel anticancer treatments. To this end, several strategies have been developed to inhibit BCL2, BCL-XL, BCL-w, and MCL1. While early clinical trials in haematological malignancies demonstrated exciting single-agent activity of BCL2-inhibitors, the response in solid tumours was limited, indicating that, in solid tumours, different strategies have to be developed in order to successfully treat patients with BCL2-inhibitors. In this review, the function of the different antiapoptotic BCL2-proteins and their role in solid tumours will be discussed. In addition, a comprehensive analysis of current small molecules targeting these antiapoptotic BCL2-proteins (e.g., ABT-737, ABT-263, ABT-199, TW-37, sabutoclax, obatoclax, and MIM1) will be provided including a discussion of the results of any clinical trials. This analysis will summarise the potential of BCL2-inhibitors for the treatment of solid tumours and will unravel novel approaches to utilise these inhibitors in clinical applications.

Figure 1

Apoptotic signalling pathways. In the extrinsic pathway, apoptosis can be initiated at the cell surface by ligation of death receptors. This results in the activation of caspase-8 at the death inducing signalling complex (DISC) and, in some circumstances, cleavage of the BH3-only protein BID. In the intrinsic pathway, apoptosis is initiated at the mitochondria and is regulated by BCL2-proteins. Activation of the intrinsic pathway, for example, by cellular stress, results in loss of mitochondrial membrane potential, release of cytochrome c, and activation of caspase-9 in the Apaf-1 containing apoptosome. Both pathways converge into the activation of the executioner caspases, for example, caspase-3. Caspases may be inhibited by the Inhibitor of apoptosis proteins (IAPs).

Figure 2

The BCL2-family. The multidomain proapoptotic proteins BAX and BAK mediate the release of cytochrome c from mitochondria into cytosol. They are inhibited by the antiapoptotic BCL2-proteins (BCL2, BCL-X_L, BCL-w, MCL1, and BCL2A1). BH3-only proteins (e.g., BIM, BID, PUMA, BAD, BMF, and NOXA) can neutralize the function of the antiapoptotic BCL2-proteins and may also directly activate BAX and BAK.

Figure 3

Small molecule BCL2-inhibitors. Inhibition of multiple or individual antiapoptotic BCL2-proteins by small molecule antagonists.