Single-cell transcriptional and chromatin accessibility profiling reveals therapeutic vulnerabilities in chronic lymphocytic leukemia

Targeting of Bruton's tyrosine kinase (BTK) has revolutionized the treatment of chronic lymphocytic leukemia (CLL). However, resistance emerges when the cells acquire mutations that abrogate drug binding or activate signaling by mechanisms independent of its kinase activity. To identify potential therapeutic vulnerabilities in patients resistant to both covalent BTKi and venetoclax, we analyzed single-cell transcriptome profiling (scRNA-seq) and single-cell chromatin mapping (scATAC-seq) in patient samples. We identified upregulation of the B-cell receptor (BCR) signaling pathway within the CLL cells. Within these cells, we saw an upregulation in PRKCB expression and highly accessible chromatin at its promoter. To therapeutically target PKCB, we utilized MS-553, an ATP-competitive, reversible inhibitor of PKCB. We found that inhibition of PKCB with MS-553 inhibited critical BCR, NF-kB, and Wnt signaling in treatment-naive and BTKi-resistant patient samples. Furthermore, we explored potential combination therapeutic approaches of MS-553 with venetoclax and established this strategy as a potential treatment for CLL patients.