Exceptional Response to BTK Inhibitors in Aggressive Lymphomas Linked to Chronic Selective Autophagy

Diffuse large B cell lymphoma is an aggressive cancer type that is profoundly heterogeneous, both molecularly and phenotypically, presenting a challenge for precision medicine. Inhibitors of the kinase BTK block B cell receptor (BCR)-dependent NF-ï«B signaling and are particularly effective in certain molecular subtypes of DLBCL, but the underlying mechanisms are poorly understood. The MCD genetic subtype, which often acquires mutations targeting the BCR subunit CD79B and MYD88, typically resists chemotherapy but responds exceptionally to BTK inhibitors. By functional proteogenomics, we discovered a non-canonical form of chronic active selective autophagy in MCD DLBCL that targets ubiquitinated mutant MYD88, an adaptor protein essential for oncogenic NF-ï«B survival signaling, for degradation. Moreover, MCD tumors acquire genetic and epigenetic alterations that attenuate this novel tumor suppressive pathway. Importantly, BTK inhibitors activated this chronic selective autophagy pathway to degrade MYD88, thus explaining the exceptional benefit of BTK-targeted therapies in the MCD DLBCL subtype.