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 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.
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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