Targeting Inhibitor of Apoptosis Proteins to Overcome Chemotherapy Resistance-A Marriage between Targeted Therapy and Cytotoxic Chemotherapy

Abstract

Precision oncology is the ultimate goal of cancer treatment, i.e., to treat cancer and only cancer, leaving all the remaining cells and tissues as intact as possible. Classical chemotherapy and radiotherapy, however, are still effective in many patients with cancer by effectively inducing apoptosis of cancer cells. Cancer cells might resist apoptosis via the anti-apoptotic effects of the inhibitor of apoptosis proteins. Recently, the inhibitors of those proteins have been developed with the goal of enhancing the cytotoxic effects of chemotherapy and radiotherapy, and one of them, xevinapant, has already demonstrated effectiveness in a phase II clinical trial. This class of drugs represents an example of synergism between classical cytotoxic chemo- and radiotherapy and new targeted therapy.

Keywords: XIAP; apoptosis; cIAP1; cIAP2; cancer; tolinapant; xevinapant.

Figure 1

Selected mechanisms of action of chemotherapy and radiotherapy and the role of inhibition of apoptosis proteins (IAPs) and their physiological (Smac) and pharmacological (xevinapant, birinapant, tolinapant, others) inhibitors. Based on [8,24]. Abbreviations: Smac—second mitochondrial activator of caspases, IAP—inhibitor of apoptosis proteins, cIAP1 and cIAP2—cellular inhibitor of apoptosis proteins 1 and 2, XIAP—X-linked inhibitor of apoptosis protein.

Figure 2

The intrinsic pathway of apoptosis (left-hand side of the figure, highlighted in light green) is triggered via intracellular stress, such as DNA damage triggered via chemotherapy or radiotherapy. The mitochondria are fundamental in this process, as later steps depend on the release of pro-apoptotic molecules (cytochrome C and Smac) via the mitochondria. The release of cytochrome C and Smac (and, by extension, apoptosis) is prevented via proteins of the BCL family, such as BCL-2, MCL1, and BCL-XL. These apoptosis inhibitors can be inhibited via the endogenous BH3 or an exogenous analog, such as the BH3-mimetic venetoclax. The proteins of the BCL family inhibit the BAX and BAK channels, which regulate the permeability of the mitochondrial membrane. Once this inhibition is lifted, BAX and BAK increase the membrane permeability, leading to the release of cytochrome C and Smac, which activates the caspase cascade. This process can be inhibited via XIAP, which directly inhibits the Caspase 3/7 dimer further downstream. The extrinsic pathway of apoptosis (right-hand side of the figure, highlighted in pale blue) is triggered via extracellular death receptors of the TNF superfamily, such as Apo2L/TRAIL and Fasl. The activation of these receptors via extracellular ligands leads to the activation of pro-Caspase 8 into its active form (Caspase 8). The cIAP1/2 proteins are able to poly-ubiquitinate Caspase 8 (as well as other pro-apoptotic proteins) and target them for degradation in the proteasome. Not pictured here are the remaining 5 IAPs, namely NAIP, Survivin, Bruce/Apollon, ML-IAP/Livin, and ILP-2. The reader is directed to [29,30] for a more detailed treatment of how those IAPs integrate with the apoptosis pathways. Both pathways culminate in the formation of the activated Caspase-3/7 dimer, which triggers apoptosis via a number of effector mechanisms. Abbreviations: Smac—second mitochondrial activator of caspases, Cyt.C—cytochrome C, IAP—inhibitor of apoptosis proteins, cIAP1/2—cellular inhibitor of apoptosis protein 1 and 2, XIAP—X-linked inhibitor of apoptosis protein, Ub—ubiquitin, Poly-Ub—poly-ubiquitination, BH3—BCL-2 homology domain 3, MCL1—Myeloid cell leukemia 1, BCL-XL—B-cell lymphoma-extra large, BCL-2—B-cell lymphoma 2, BAK—BCL-2 antagonist/killer, BAX—BCL-2-associated X protein.

Figure 3

Conceptual illustration of the relationship between XIAP expression and phenotypic markers of breast cancer (according to the results from the bioinformatics analysis of RNA and protein expression in breast cancer cells) which are classically associated with either chemotherapy resistance or chemotherapy sensitivity. Based on [36].