2. Academic Validation
  3. The dual HCK/BTK inhibitor KIN-8194 impairs growth and integrin-mediated adhesion of BTKi-resistant mantle cell lymphoma

The dual HCK/BTK inhibitor KIN-8194 impairs growth and integrin-mediated adhesion of BTKi-resistant mantle cell lymphoma

  • Leukemia. 2024 Mar 7. doi: 10.1038/s41375-024-02207-9.
Hildo C Lantermans 1 2 3,  Fangxue Ma 1 2 3,  Annemieke Kuil 1 2 3,  Sanne van Kesteren 1 2 3,  Sevtap Yasinoglu 1 2 3,  Guang Yang 4 5 6,  Sara J Buhrlage 7,  Jinhua Wang 7,  Nathanael S Gray 8,  Marie José Kersten 2 9,  Steven P Treon 4 5,  Steven T Pals 1 2 3,  Marcel Spaargaren 10 11 12
Affiliations

Affiliations

  • 1 Department of Pathology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
  • 2 Lymphoma and Myeloma Center Amsterdam - LYMMCARE, Amsterdam, The Netherlands.
  • 3 Cancer Center Amsterdam (CCA), Cancer Biology and Immunology - Target & Therapy Discovery, Amsterdam, The Netherlands.
  • 4 Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • 6 Blueprint Medicines, Cambridge, MA, USA.
  • 7 Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 8 Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA, USA.
  • 9 Department of Hematology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.
  • 10 Department of Pathology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands. marcel.spaargaren@amsterdamumc.nl.
  • 11 Lymphoma and Myeloma Center Amsterdam - LYMMCARE, Amsterdam, The Netherlands. marcel.spaargaren@amsterdamumc.nl.
  • 12 Cancer Center Amsterdam (CCA), Cancer Biology and Immunology - Target & Therapy Discovery, Amsterdam, The Netherlands. marcel.spaargaren@amsterdamumc.nl.
PMID: 38454120 DOI: 10.1038/s41375-024-02207-9
Abstract

Although Bruton's tyrosine kinase (Btk) inhibitors (BTKi) have significantly improved patient prognosis, mantle cell lymphoma (MCL) is still considered incurable due to primary and acquired resistance. We have recently shown that aberrant expression of the Src-family tyrosine kinase hematopoietic cell kinase (HCK) in MCL correlates with poor prognosis, and that genetic HCK perturbation impairs growth and integrin-mediated adhesion of MCL cells. Here, we show that KIN-8194, a dual inhibitor of Btk and HCK with in vivo activity against Myd88-L265P-driven diffuse large B-cell lymphoma and Waldenström Macroglobulinemia, has a potent growth inhibitory effect in MCL cell lines and primary MCL cells, irrespective of their sensitivity to BTKi (ibrutinib and acalabrutinib). In BTKi-resistant cells this is mediated by inhibition of HCK, which results in repression of AKT-S6 signaling. In addition, KIN-8194 inhibits integrin-mediated adhesion of BTKi-sensitive and insensitive MCL cells to fibronectin and stromal cells in an HCK-dependent manner. Finally, we show that MCL cells with acquired BTKi resistance retain their sensitivity to KIN-8194. Taken together, our data demonstrate that KIN-8194 inhibits growth and integrin-mediated adhesion of BTKi-sensitive MCL cells, as well as MCL cells with primary or acquired BTKi resistance. This renders KIN-8194 a promising novel treatment for MCL patients.

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