Myeloid Cell Leukemia 1, or MCL-1, is a protein found in human cells. This protein plays a role in regulating cellular processes that determine whether a cell lives or undergoes programmed death. Understanding MCL-1’s behavior is important in scientific research, particularly in the context of various diseases. Its activity is monitored as scientists work to unravel its complex functions in cellular health and disease.
MCL-1’s Normal Function
MCL-1 contributes to the survival of healthy cells by acting as an anti-apoptotic protein. It belongs to the BCL-2 family of proteins, which regulate programmed cell death, known as apoptosis. MCL-1 helps prevent cells from undergoing this self-destruction pathway, promoting cell viability. This function is important for maintaining the integrity and balance of tissues throughout the body, ensuring that necessary cells are not eliminated before their time.
The protein accomplishes its anti-apoptotic role by interacting with other proteins. MCL-1 binds to pro-apoptotic effector proteins, such as BAX and BAK, preventing them from initiating apoptosis. It also interacts with BH3-only proteins like PUMA, BIM, and NOXA, sequestering them and stopping them from activating BAX and BAK. MCL-1’s expression is tightly controlled and it has a short half-life, allowing cells to rapidly adjust their survival signals in response to changing conditions. Beyond its role in preventing cell death, MCL-1 also helps regulate other cellular processes, including cell cycle progression, DNA repair, and maintaining mitochondrial health and energy production.
MCL-1’s Role in Cancer
MCL-1’s normal cell-protective function can become a problem in the development and progression of cancer. In many types of cancer, MCL-1 is found at abnormally high levels. This increased abundance of MCL-1 provides cancer cells with a survival advantage, allowing them to evade the programmed cell death signals that would normally eliminate them.
Elevated MCL-1 enables cancer cells to survive and proliferate, contributing to tumor growth and resistance to anti-cancer treatments. Cancer cells with elevated MCL-1 levels can resist the effects of conventional chemotherapy and radiation therapies, which often work by inducing apoptosis in tumor cells. This resistance poses a challenge in oncology, as it can lead to treatment failure and disease relapse.
MCL-1 plays a role in the survival and resistance of various malignancies. It is overexpressed in several hematologic cancers, including certain leukemias, lymphomas, and multiple myeloma. The protein’s elevated presence is also observed in solid tumors, such as non-small cell lung cancer, breast cancer, pancreatic cancer, and liver cancer. In these cancers, MCL-1’s ability to suppress apoptosis makes it a factor in disease aggressiveness and poor patient outcomes.
Targeting MCL-1 in Cancer Treatment
Given its role in cancer cell survival and drug resistance, MCL-1 has emerged as a target for new cancer therapies. Therapeutic strategies are being developed to inhibit MCL-1’s anti-apoptotic activity, aiming to restore the cell’s ability to undergo programmed death. These therapies are designed to neutralize the protein’s function, making cancer cells vulnerable to destruction.
MCL-1 inhibitors, known as BH3 mimetics, work by directly binding to the MCL-1 protein. Specifically, they occupy the BH3-binding groove on MCL-1, where MCL-1 normally binds to and sequesters pro-apoptotic proteins like BAX, BAK, and BIM. By competitively binding to this site, the inhibitors prevent MCL-1 from interacting with these pro-death proteins, effectively releasing them.
Once released, the pro-apoptotic proteins are free to activate the apoptotic cascade, leading to the selective death of cancer cells dependent on MCL-1 for survival. This mechanism aims to re-sensitize cancer cells to apoptotic signals, allowing them to respond to existing therapies or to be eliminated as a standalone treatment. The development of these inhibitors represents a focused approach to cancer treatment, selectively targeting a molecular vulnerability in tumor cells.
Developing MCL-1-Targeting Therapies
The development of therapies that target MCL-1 involves addressing several challenges. One challenge is ensuring the specificity of MCL-1 inhibitors to avoid affecting healthy cells. While MCL-1 overexpression benefits cancer cells, normal cells also rely on MCL-1 for their survival. Inhibiting MCL-1 too broadly could lead to dose-limiting side effects.
A side effect observed in early clinical trials of some MCL-1 inhibitors has been cardiotoxicity, indicated by increased cardiac troponin levels, a marker of heart damage. This has led to the discontinuation of some drug development programs, requiring careful monitoring and further research. Despite these challenges, researchers continue to explore various strategies, including small molecule inhibitors, proteolysis-targeting chimeras (PROTACs) for MCL-1 degradation, and antisense oligonucleotides (ASOs) to reduce MCL-1 expression.
Ongoing research also focuses on combination therapies, where MCL-1 inhibitors are used alongside other treatments to enhance efficacy and overcome drug resistance. Combining MCL-1 inhibitors with BCL-2 inhibitors has shown synergistic effects in preclinical studies. Many MCL-1 inhibitors have progressed into clinical trials, primarily Phase I studies for various cancers. These trials aim to assess the safety, tolerability, and antitumor activity of these compounds, moving them closer to potential clinical application.