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Abstract Disparate pathogenic mechanisms complicate precision-medicine efforts to treat diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis. Though potentially curable with frontline combination chemoimmunotherapy, 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 is resistant to multiple additional drug classes, demonstrating urgency to derive mechanistically rooted strategies to overcome undruggable BCL10 mutants that stabilize 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 anti-apoptotic genes increases mitochondrial membrane potential, underlying multidrug resistance. Increased expression of BCL2, BCL2L1 (BCL-XL), and BCL2A1 (BFL1) drives resistance to venetoclax, but expression can be overcome by the potent non-covalent BTK inhibitor pirtobrutinib. Venetoclax plus pirtobrutinib synergized in overcoming resistance and potently killed BCL10-mutant lymphomas in vitro and in vivo. BTK therefore retains key roles protecting DLBCL from apoptosis even when downstream activation of the BCL10 signaling complex activates NF-kB independently.

Refractory cancer recurrence in patients is a serious challenge in modern medicine. Tumor regrowth in a more aggressive and invasive drug-resistant form is caused by a specific sub-population of tumor cells defined as cancer stem cells (CSCs). While the role of CSCs in cancer relapse is recognized, the signaling pathways of CSCs-driven chemoresistance are less well understood. Moreover, there are no effective therapeutic strategies that involve specific inhibition of CSCs responsible for cancer recurrence and drug resistance. There is a clinical need to develop new therapies for patients with refractory sarcomas, particularly fibrosarcoma. These aggressive tumors, with poor overall survival, do not respond to conventional therapies. Standard systemic chemotherapy for these tumors includes doxorubicin (DOX). A Tyr peptide analog (TPA), developed in our laboratory, specifically targets CSCs by drastically reducing expression of the polycomb group protein enhancer of zester (EZH2) and its downstream targets, specifically ALDH1A1 and Nanog. In vivo experiments demonstrated that TPA inhibited tumor growth in nu/nu mice with relapsed DOX-treated fibrosarcoma 7-fold and led to improved overall (2-fold) survival. In an experimental metastatic model, the combination of TPA with DOX treatment extended overall survival 3-fold, suggesting that targeting CSC can become an effective strategy in the treatment of refractory/relapse fibrosarcoma.