Inhibition of MCL-1, an anti-apoptotic protein, is a promising therapeutic strategy in the treatment of multiple myeloma. Moreover, amplification of locus 1q21 may have diagnostic potential as a marker to predict MCL-1 inhibitor sensitivity in patients with multiple myeloma. These were the main conclusions drawn by Anne Slomp who defended her PhD research on September 9 in Utrecht.
Resistance to apoptosis enables malignant cells to survive in the presence of otherwise lethal chromosomal, cellular, and metabolic alterations. As a consequence, dependence on anti-apoptotic proteins is a potentially targetable weakness of cancer cells. The research described in the thesis of Anne Slomp (Center for Translational Immunology, UMC Utrecht) focuses on the anti-apoptotic BCL-2 family protein MCL-1 as a therapeutic target in multiple myeloma (MM, bone marrow cancer), because MM is characterized by high expression of MCL-1.
Key findings
In her research, performed in the research group of dr. Victor Peperzak, Anne Slomp addressed the relative roles of apoptosis inhibitors MCL-1, BCL-2, and BCL-XL during the different stages of B cell development and plasma cell (PC) differentiation in healthy cells as well as in MM. Key findings of this thesis are:
- BCL-XL was found to be important for survival of immature B cells, while BCL-2 is important for survival of mature B cells and long-lived PC. MCL-1, in contrast, is important for survival throughout B cell development, and reduced expression of MCL-1 sensitizes PC to BCL-2 and BCL-XL inhibition.
- MM cells from patients with amplification of 1q21, the locus that contains the MCL-1 gene, are significantly more sensitive to treatment with an MCL-1 inhibitor than MM cells without this chromosomal aberration. This finding indicates that 1q21 amplification can be used as a predictive marker to guide selection of therapy.
- Because MCL-1 is important for survival of many cell types besides MM cells, clinical targeting of MCL-1 using specific MCL-1 inhibitors may lead to undesired side-effects. One way to circumvent such side-effects is by targeting MCL-1 indirectly, thereby exploiting cancer- or tissue-specific characteristics of MCL-1 regulation in MM. Proteasome inhibitors, such as bortezomib (Velcade), are often considered indirect MCL-1 inhibitors because they induce upregulation of NOXA (a pro-apoptotic BCL-2 protein selective for MCL-1). Anne Slomp showed that bortezomib-induced apoptosis in MM does in fact not require NOXA. In addition, degradation of MCL-1 upon bortezomib treatment was independent from NOXA expression and a consequence, rather than the cause, of caspase activation.
- Molecular regulation of MCL-1 was studied, with the aim to identify phosphatases that stabilize MCL-1 in MM. MCL-1 half-life was increased in a subset of MM and diffuse large B cell lymphoma (DLBCL) cell lines, and in MM patient samples. MCL-1 protein levels in MM and DLBCL reflect transcriptional activity as well as protein half-life, and the relative contribution of these processes differs per cell line. The protein phosphatase complex PP2A was identified as an important stabilizer of MCL-1. Therefore, PP2A inhibition may prove effective as a strategy to indirectly inhibit MCL-1 in MM.
- Inhibition of MCL-1 is a strategy for treatment of cancers that depend on MCL-1 for survival, but this strategy may also be used for cells that have become resistant to other killing pathways. Anne Slomp describes the widespread expression of SerpinB9 across lymphomas and other cancers. SerpinB9 expression renders tumor cells resistant to granzyme B-mediated killing by NK cells and gene engineered T cells, such as chimeric antigen receptor T cells (CAR-T cells), and expression of SerpinB9 may thus predict effectiveness of immunotherapy. Since granzyme B-resistant tumor cells were still sensitive to inhibition of anti-apoptotic proteins, such as MCL-1, targeting these anti-apoptotic proteins directly may circumvent resistance to immunotherapy with engineered T or NK cells.
In conclusion, inhibition of the anti-apoptotic protein MCL-1 is a promising therapeutic strategy in MM. Further studying the complex regulation of MCL-1 will aid in finding new rational drug combinations that can exploit MCL-1 dependence and induce apoptosis in MM, and potentially in other cancer types as well.
Multiple Myeloma
Multiple myeloma is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Initial symptoms are bone pain, bleeding, infections, and anemia. The cause of MM is unknown, but risk factors include obesity, radiation exposure and family history. MM is considered treatable, but generally incurable. Remission may be induced with steroids, chemotherapy, targeted therapy, and stem cell transplant. In the Netherlands, the disease is diagnosed in approx. 1.200 people each year, with a slight overrepresentation of men. Without treatment, typical survival is 7 months, whereas with current treatments, survival is usually 4-5 years.
PhD defense
Anne Slomp (1993, Eindhoven) received her PhD on September 9, 2020 at Utrecht University. The title of her thesis was “A matter of life or death: targeting MCL-1 in multiple myeloma”. Supervisor was prof. dr. Monique Minnema (Department of Medical Oncology, UMC Utrecht). Co-supervisor was dr. Victor Peperzak (Center for Translational Immunology, UMC Utrecht). Anne Slomp works as an Associate Medical Publications Manager at Excerpta Medica in Amsterdam.
