New Strategies Aim at Survival Protein MCL-1

Jane De Lartigue, PhD
Published: Thursday, May 24, 2018
Myeloid cell leukemia 1 (MCL-1), a key signaling protein in cancer cell survival pathways, has emerged as an intriguing target for anticancer drug development as researchers turn their attention to strategies directed at evasion of apoptosis, a distinguishing characteristic of cancer.

As part of the B-cell lymphoma-2 (BCL-2) family of proteins, MCL-1 is among the central coordinators of apoptosis. The ability to evade apoptosis, whereby cancer cells thrive amid the stresses of oncogenesis, is characterized as a hallmark of cancer because it is one of the unique acquired abilities that allow the malignant transformation of a normal cell.

Figure. Signaling Networks Active in Apoptosis

In 2016, venetoclax (Venclexta) became the first BCL-2 inhibitor to gain FDA approval, with an indication for patients with relapsed and refractory chronic lymphocytic leukemia (CLL). Despite this success, resistance to BCL-2 inhibition develops and is frequently mediated by alterations in other BCL-2 protein family members. In particular, MCL-1 overexpression is one of the most common molecular aberrations observed in many types of cancer.

The development of MCL-1 inhibitors has proved challenging but at last appears to be bearing fruit. Both direct inhibition through small-molecule MCL-1–specific inhibitors and indirect targeting through blockade of cyclindependent kinase 9 (CDK9) are showing promise in the early stages of development in a range of cancer types. Additionally, pairing MCL-1 inhibitors with venetoclax displays synergistic activity and could help mitigate acquired resistance. They also may be highly effective combined with other targeted drugs and with standard-of-care agents.

The next major challenge will be the identification of accurate predictive biomarkers to help guide the optimal clinical application of MCL-1 inhibitors and other drugs targeting this family of survival proteins.

Tight Regulation of Cell Death

Apoptosis is a tightly controlled form of cell death that clears unwanted or damaged cells and maintains tissue homeostasis, without breaching the plasma membrane or releasing potentially damaging cellular contents.

Two major pathways induce apoptosis— extrinsic and intrinsic—which, as their names suggest, are triggered by extra- and intracellular cues, respectively. The intrinsic pathway is conducted primarily by the BCL-2 family, a group of more than a dozen proteins that share conserved sequences known as BCL-2 homology (BH) domains. They can be divided into 3 groups of proteins: antiapoptotic, proapoptotic (BH3-only), and proapoptotic (effector). These proteins interact with one another to create a delicate balance of pro- and antiapoptotic signals that govern the cell’s fate.

The antiapoptotic BCL-2 proteins include BCL-2, after which the family is named, as well as BCL-XL, BCL-W, MCL-1, and BFL/A1. The proapoptotic proteins can be further subdivided into those that share just a BH3 domain: the BH3-only proteins, which include BID, BAD, BIK, PUMA, and NOXA, and the effector proteins— BAK, BAX, and BOK.

In healthy cells, the proapoptotic effector proteins are bound and sequestered by the antiapoptotic proteins, keeping their activity in check. In response to stimuli such as DNA lesions, mitotic defects, and oxidative stress, the BH3-only proapoptotic proteins are upregulated. They bind to the antiapoptotic proteins and block their suppression of the proapoptotic effector proteins, particularly BAK and BAX. Several of the BH3-only proteins can also directly activate BAK and BAX.

BAK and BAX subsequently oligomerise and form pores within the mitochondrial membrane, allowing cytochrome c to be released into the cytoplasm. Cytochrome c drives the formation of the apoptosome, a protein complex that activates caspase-9, which in turn activates other effector caspases.

Caspases are proteases that break down key intracellular proteins, driving characteristic apoptotic outcomes, including fragmentation of the DNA, shrinking of the cell, and blebbing of the membrane. It culminates in the cell breaking up into apoptotic bodies that are engulfed by the phagocytes of the immune system1-5 (Figure6).

A Cancer Hallmark

The apoptotic program is a vital component in the development and maintenance of a healthy organism. However, disruption of the program’s checks and balances can have pathologic effects. An acquired ability to evade apoptosis is a characteristic of cancer cells, permitting them to grow unchecked, even in the presence of cancerinduced DNA damage or cellular stress, and can help them resist anticancer therapy.

One of the central coordinators of apoptosis is the tumor suppressor protein p53. Among its myriad functions is the detection of the cellular conditions required to trigger apoptosis, such as DNA damage, earning it the nickname “guardian of the genome.” A mutated or missing TP53 gene is one of the most common ways by which tumor cells evade apoptosis.

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