PKCβ Inhibitor MS-553 Displays Preclinical Efficacy in Both Treatment-Naïve and BTK Inhibitor–Resistant Chronic Lymphocytic Leukemia

Abstract Inhibition of the tyrosine kinase BTK is a major therapeutic strategy for treating B-cell malignancies, including chronic lymphocytic leukemia (CLL). However, resistance can emerge when tumor cells acquire mutations that abrogate drug binding or when BTK activates B-cell receptor (BCR) signaling by mechanisms independent of its kinase activity. In this study, we identified upregulation of PKCβ in samples from patients with CLL resistant to BTK inhibitors (BTKi) and characterized the PKCβ inhibitor MS-553. MS-553 reduced BCR and Wnt/β-catenin signaling, overcame stromal cell mediated protection, and synergized with venetoclax in CLL samples. MS-553 also retained the cytotoxicity and inhibition of both BCR and Wnt/β-catenin signaling in models (cell lines and primary samples) of covalent BTKi-resistant (C481S BTK) and noncovalent BTKi-resistant (T474I or L528W BTK) CLL. Furthermore, MS-553 delayed disease progression and prolonged survival in the Eμ-MTCP1 murine model of CLL. Collectively our results demonstrate that selective inhibition of PKCβ has the potential to overcome BTKi-resistant CLL. Significance: This study identified and characterized PKCβ as a therapeutic target in CLL, including CLL resistant to BTKis. Inhibition of PKCβ suppressed both BCR and Wnt/β-catenin signaling, delayed disease progression in vivo, overcame BTKi resistance mechanisms, and enhanced response to BCL-2 inhibition. See related commentary by Jebaraj and Stilgenbauer, p. 21