Targeting apoptotic pathways for cancer therapy

Abstract

Apoptosis is a form of programmed cell death that is mediated by intrinsic and extrinsic pathways. Dysregulation of and resistance to cell death are hallmarks of cancer. For over three decades, the development of therapies to promote treatment of cancer by inducing various cell death modalities, including apoptosis, has been a main goal of clinical oncology. Apoptosis pathways also interact with other signaling mechanisms, such as the p53 signaling pathway and the integrated stress response (ISR) pathway. In addition to agents directly targeting the intrinsic and extrinsic pathway components, anticancer drugs that target the p53 and ISR signaling pathways are actively being developed. In this Review, we discuss selected and promising anticancer therapies in various stages of development, including drug targets, mechanisms, and resistance to related treatments, focusing especially on B cell lymphoma 2 (BCL-2) inhibitors, TRAIL analogues, DR5 antibodies, and strategies that target p53, mutant p53, and the ISR.

Figure 1. Intrinsic and extrinsic apoptosis pathways.

(A) Intrinsic apoptosis pathways. Upon activation, BAK and BAX undergo conformational changes and oligomerization, forming pores in the MOM and causing irreversible MOM permeabilization (MOMP), the critical step for intrinsic apoptosis (3), allowing release of cytochrome c and SMAC. Cytochrome c and dATP join APAF-1 and the initiator protein procaspase-9 to form the apoptosome, while SMAC interacts with IAPs (see below). Within the apoptosome, procaspase-9 is cleaved into active caspase-9, which cleaves and activates the apoptosis effector proteins caspase-3, -6, and -7 (3). (B) Extrinsic apoptosis pathway. Upon ligand binding, DR4 and DR5 trimerize and aggregate within the cell membrane, a process known as capping. This is followed by recruitment of the adaptor protein FADD, which has a death effector domain (DED). Initiator procaspase-8 and -10 also have DEDs that bind to FADD at its DED, forming the DISC. Procaspase-8 and -10 are activated within the DISC and in turn cleave and activate executioner caspase-3, -6, and -7. Activation of procaspase-8/10 is negatively regulated by c-FLIP. c-FLIP competes directly with procaspase-8 for binding to FADD through homotypic DED interactions, thus inhibiting procaspase-8 recruitment and activation at the DISC (9-12). Activated caspase-8 also cleaves the BH3 subfamily member BID to active form truncated-BID (tBID). tBID translocates to the MOM and initiates apoptosis through its interactions with proapoptotic effector proteins BAK and BAX. BID cleavage and translocation to the mitochondria link the extrinsic cell death pathway to the intrinsic apoptotic pathway and amplify the apoptotic response. This amplification mechanism is required for effective apoptosis in certain cells, denoted as type II cells for their mechanism of apoptosis, in contrast with type I cells, which undergo extrinsic apoptosis independently of intrinsic apoptosis pathway induction (13, 14).

Figure 2. Targets in the intrinsic and extrinsic apoptosis pathways.

(A) Interactions of the BCL-2 protein family. The multi-BH domain family members either suppress apoptosis (e.g., BCL-2, BCL-XL, and MCL-1) or promote apoptosis (e.g., BAX, BAK), whereas the BH3-only subfamily members identified to date (e.g., BAD, BID, PUMA, NOXA, and BIM) function exclusively to promote cell death (3, 4) BH3-only proteins can be divided into activators or sensitizers. The activators PUMA, tBID, and BIM directly activate BAK and BAX and interact with antiapoptotic proteins to promote MOMP (5, 6). In contrast, the sensitizers BAD and NOXA only interact with the antiapoptotic proteins and do not activate BAK and BAX (7, 8). Interactions with antiapoptotic BCL-2 proteins and activator BH3-only proteins regulate BAK and BAX activity. (B) High-potency TRAIL receptor agonists. ABBV-621 is a hexavalent TRAIL fusion protein with Fc-FcγR interactions disabled by IgG Fc D297S mutation. INBRX-109 is a tetravalent DR5 agonistic antibody with Fc effector function disabled by forming a cycle.

Figure 3. Strategies targeting p53 and mutant p53.

(A) Reactivation of mutant p53. Direct binding of a small molecule (gray boxes) to a mutant p53 promotes and stabilizes WT p53 folding and conformation, leading to restoration of specific DNA binding and transcription of p53 target genes. This will induce tumor cell apoptosis or senescence. (B) Inhibition of MDM2. MDM2 binds to p53 directly through its N-termini and inhibits p53 function through two major mechanisms: (a) upon binding, MDM2 ubiquitinates p53, promoting proteasomal degradation of p53; (b) MDM2 promotes export of p53 out of the cell nucleus. (C) Depletion of mutant p53. Small molecules inhibit MTp53 gain-of-function and dominant-negative effects through degradation of MTp53.

Figure 4. Targeting the ISR and overcoming resistance mechanisms.

From top left: in the cell death pathway of the ISR, ATF4 induction can be achieved by eIF2α kinase activators, such as bortezomib, carfilzomib, and imipridones (gray boxes). ATF4 directly or indirectly through the induction of transcriptional factors CHOH or ATF3 regulates the expression of proapoptotic genes, such as DR5, PUMA, NOXA and BIM, which promotes cell apoptosis (lower right). Resistance mechanisms include movement of the PUP-HDAC6-dynein complex to aggresome along the microtubule (upper right). The aggresome is ultimately degraded in lysosomes. Additionally, ER stress induced by the proteasome inhibitors can also promote HDAC4 binding to ATF4 to prevent its nuclear translocation and inhibit ATF4 transcriptional activity.