Bruton’s tyrosine kinase inhibition re-sensitizes multidrug-resistant DLBCL tumors to venetoclax

Disparate mechanisms of pathogenesis have thwarted implementation of precision medicine approaches for the treatment of diffuse large B-cell lymphoma (DLBCL), the most frequently diagnosed hematologic malignancy in the United States. Though curable with combination chemoimmunotherapy in many newly diagnosed patients, DLBCL carries persistently poor prognosis for those with relapsed or refractory (rel/ref) disease, despite recent advances in immunotherapy. Here, we build on recent findings implicating gain-of-function mutations in the BCL10 signaling protein as drivers of resistance to Bruton’s tyrosine kinase (BTK) inhibitors. We show mutant BCL10-driven DLBCL models are resistant to multiple additional drug classes, demonstrating urgency to derive mechanistically rooted treatment strategies to overcome undruggable BCL10 mutants that form stable BTK-independent signaling filaments upstream of NF-kB activation. BCL10 mutants promote a cytokine-reinforced positive feedback loop of lymphomagenesis driving not just NF-kB but multiple additional pathways converging on diffuse activation of oncogenic transcription factors. Up-regulation of multiple anti-apoptotic genes promotes increased mitochondrial membrane potential, a key factor underlying multidrug resistance. Increased expression of BCL2, BCL2L1 (BCL-XL), and BCL2A1 (BFL1) drives resistance to the BCL2 inhibitor venetoclax, but further investigation revealed expression is overcome by the potent non-covalent BTK inhibitor pirtobrutinib. Venetoclax plus pirtobrutinib synergized in overcoming resistance and potently killed BCL10- mutant DLBCL tumors in vitro and in vivo. BTK therefore retains key roles protecting DLBCL tumors from apoptosis even when direct downstream activation of the BCL10 signaling complex activates NF-kB independently.