Mantle cell lymphoma (MCL) is an aggressive type of Non-Hodgkin Lymphoma (NHL) that comprises of fast-growing malignant B lymphocytes that swiftly spread throughout the body, triggering symptoms rapidly. In the Netherlands, over 200 individuals are diagnosed with MCL each year, with most patients over 50 years of age.
In recent years, the life expectancy for individuals with MCL has increased, following the introduction of rituximab immunotherapy, a monoclonal antibody that binds the CD20 surface molecule on cells from the B cell lineage and empowers the detection and elimination of MCL cells by the immune system. Other treatments include stem cell transplantation and, more recently, specific targeted therapy with Bruton’s tyrosine kinase (BTK) inhibitors. However, despite these advances, MCL is still considered incurable due to primary and acquired therapy resistance, highlighting a need for better curative treatments.
Specifically Targeting Cancer Biology
It has been known for decades that malignant cells can hijack various natural cell biology mechanisms to help them grown uncontrollably. The challenge is to identify which mechanisms tumor cells have corrupted so effective therapies can be developed. In mantle cell lymphoma, it was uncovered that the B-cell receptor signaling pathway - involved in normal B-cell development, immune activation, and cell survival - is deregulated and promotes rapid cell growth through activation of BTK.
Dr. Marcel Spaargaren, principal investigator at Cancer Center Amsterdam and senior author of the recent publication says: “We have previously revealed that the small molecule BTK inhibitor ibrutinib exerts unprecedented anti-lymphoma activity via very specific molecular mechanisms. Besides directly reducing MCL growth, BTK inhibitors repress the integrin-mediated adhesion of MCL cells to the lymphoid microenvironment. Consequently, the malignant cells are evicted from these protective niches into the peripheral blood, depriving them from critical growth and survival factors.”
Blocking Tumor Growth
While BTK inhibitors (BTKi) pack an initial powerful punch, primary drug resistance is seen in about 30% of MCL patients and upon prolonged treatment acquired drug resistance develops in many other patients over time. The team’s strategy is to identify additional tumor-hijacked pathways to further undermine the cancer’s growth. “There are other deregulated pathways in MCL that promote growth,” says Hildo Lantermans, a PhD candidate in Spaargaren’s research team and first author of the study. “In 2021, we showed that aberrant expression of the Src-family tyrosine kinase HCK - hematopoietic cell kinase - in MCL correlates with poor prognosis, and that genetic perturbation of HCK impairs growth and integrin-mediated adhesion of MCL cells.”
Doubling Down on MCL
In their latest scientific paper published in the journal Leukemia, the authors describe the impact of a new small molecule inhibitor KIN-8194 that targets both BTK and HCK.
“To test the new KIN-8194 dual inhibitor, we initially used a panel of MCL cell lines in our laboratory,” explains Hildo. “We found that KIN-8194 inhibited the growth of all our MCL cell lines, even those with primary resistance to BTK inhibitors.” The authors show that MCL cells directly taken from patients also display reduced growth after KIN-8194 exposure.
“Moreover, MCL cells with acquired BTKi resistance retain their sensitivity to KIN-8194, and KIN-8194 inhibits integrin-mediated adhesion of BTKi-sensitive and insensitive MCL cells to fibronectin and stromal cells in an HCK-dependent manner,” adds Dr. Spaargaren. “Taken together, our data demonstrate that KIN-8194 inhibits the growth and integrin-mediated adhesion of BTKi sensitive MCL cells, as well as MCL cells with primary or acquired BTKi resistance, rendering this new inhibitor a potential promising novel treatment for MCL patients.”
For more information, contact Marcel Spaargaren, or read the publication:
Lantermans, H.C., Ma, F., Kuil, A. et al. The dual HCK/BTK inhibitor KIN-8194 impairs growth and integrin-mediated adhesion of BTKi-resistant mantle cell lymphoma. Leukemia (2024). https://doi.org/10.1038/s41375-024-02207-9
Funding
This work is supported by grants from Lymph&Co, the IWMF, and the Dutch Cancer Society (KWF).
Involved Researchers at Cancer Center Amsterdam
Hildo C. Lantermans
Fangxue Ma
Annemieke Kuil
Sanne van Kesteren
Sevtap Yasinoglu
Marie José Kersten
Steven T. Pals
Marcel Spaargaren
Text by Henri van de Vrugt.
This article was created for Cancer Center Amsterdam.
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