Targeting HCK to Overcome Ibrutinib Resistance in MYD88-Mutated B-Cell Lymphomas

The abstract discusses the role of activating mutations in MYD88 and BCR in the transactivation of Bruton's tyrosine kinase (BTK) in Waldenström macroglobulinemia (WM) and ABC DLBCL cells. Ibrutinib, a covalent inhibitor, is effective against MYD88 mutated WM and ABC-DLBCL but resistance can develop due to BTKCys481 mutations. Hematopoietic cell kinase (HCK) is implicated in survival signaling pathways and is upregulated by MYD88 mutations. A study was conducted to explore the potential of inhibiting HCK to overcome ibrutinib resistance in MYD88 mutated B-cell lymphomas.

A screening process identified a lead compound, KIN-8193, a type-II kinase inhibitor with high potency and selectivity. It demonstrated strong biochemical and cellular potency, with a molecular weight of approximately 600 and a high selectivity score. Target engagement was confirmed through a competitive ATP-biotin binding assay. The compound showed excellent metabolic stability and oral bioavailability in animal models, with a long half-life and high maximum concentration.

Toxicology studies indicated good tolerability with no significant inhibition against a panel of receptor targets, including hERG. KIN-8193 effectively inhibited the phosphorylation of HCK and its downstream target BTK in both wild-type and ibrutinib-resistant cell lines, with target engagement studies indicating binding to HCK but not BTK.

In vivo studies using a WM xenograft mouse model showed potent inhibition of HCK and BTK phosphorylation following KIN-8193 administration. Importantly, KIN-8193 selectively targeted MYD88 mutated cells, including those with BTKCys481 mutations, without affecting healthy B- and T-cells.

The study concludes with the identification of a novel HCK inhibitor, KIN-8193, which is well-tolerated and demonstrates selective killing of MYD88 mutated cells, overcoming ibrutinib resistance through the inhibition of both wild-type and mutated BTK activity.