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

Publisher: Nature Publishing Group, Specialist Journals Country of Publication: England NLM ID: 8704895 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5551 (Electronic) Linking ISSN: 08876924 NLM ISO Abbreviation: Leukemia Subsets: MEDLINE

Publication: 2000- : London : Nature Publishing Group, Specialist Journals
Original Publication: [Baltimore, Md.] : Williams & Wilkins, [c1987-

Lymphoma, Mantle-Cell*/drug therapy ; Lymphoma, Mantle-Cell*/pathology ; Lymphoma, Mantle-Cell*/metabolism ; Lymphoma, Mantle-Cell*/genetics ; Cell Adhesion*/drug effects ; Drug Resistance, Neoplasm*/drug effects ; Agammaglobulinaemia Tyrosine Kinase*/antagonists & inhibitors ; Proto-Oncogene Proteins c-hck*/metabolism ; Proto-Oncogene Proteins c-hck*/genetics ; Proto-Oncogene Proteins c-hck*/antagonists & inhibitors ; Integrins*/metabolism ; Cell Proliferation*/drug effects ; Protein Kinase Inhibitors*/pharmacology; Humans ; Cell Line, Tumor ; Pyrimidines/pharmacology ; Adenine/analogs & derivatives ; Adenine/pharmacology ; Signal Transduction/drug effects

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.
(© 2024. The Author(s).)

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7873 KWF Kankerbestrijding (Dutch Cancer Society)

EC 2.7.10.2 (Agammaglobulinaemia Tyrosine Kinase)
EC 2.7.10.2 (Proto-Oncogene Proteins c-hck)
0 (Integrins)
0 (Protein Kinase Inhibitors)
EC 2.7.10.2 (BTK protein, human)
0 (Pyrimidines)
EC 2.7.10.2 (HCK protein, human)
JAC85A2161 (Adenine)

Date Created: 20240307 Date Completed: 20240702 Latest Revision: 20240723

20240723

PMC11216997

10.1038/s41375-024-02207-9

38454120