Targetable Vulnerabilities in MYC‐Driven B Cell Lymphomas Resistant to BCR Extinction

ABSTRACT Polatuzumab vedotin, an antibody‐drug conjugate (ADC) targeting the B cell receptor (BCR) signaling subunit CD79B, has recently entered frontline therapy for diffuse large B cell lymphoma (DLBCL) and high‐grade B cell lymphoma (HGBCL), achieving encouraging clinical results. However, MYC‐driven B cell lymphomas, particularly HGBCL with MYC and BCL2 rearrangements, frequently silence surface BCR/CD79B expression, limiting the therapeutic reach of CD79B‐directed ADCs and underscoring the need for complementary treatment strategies. To uncover drug vulnerabilities associated with BCR extinction in aggressive B cell lymphomas, we conditionally ablated surface BCR expression in the λ ‐MYC mouse B cell lymphoma model and screened 1475 small‐molecule compounds, including clinically approved agents, on syngenic BCR‐positive and BCR‐negative tumor cells. This screening revealed compounds with comparable activity across both states as well as compounds with improved efficacy against BCR‐deficient lymphomas. Notably, inhibitors of mTORC1/2 and CDK4/6 displayed robust and reproducible potency in BCR‐negative lymphoma cells. Mechanistically, BCR loss impaired mTOR‐dependent anabolic control, reducing protein synthesis, while diminished Cyclin D3 abundance sensitized tumor cells to pharmacological CDK4/6 blockade. Human BCR‐negative HGBCL with MYC and BCL2 rearrangements similarly exhibited sub‐micromolar sensitivity to mTORC1/2 and CDK4/6 inhibitors. Overall, our results uncover targetable vulnerabilities in MYC‐driven B cell lymphomas, possibly extending to other aggressive B cell tumors silencing BCR expression. The data provide a rational basis for integrating CD79B‐directed ADCs with mTOR or CDK4/6 inhibitors to prevent or overcome treatment resistance of aggressive B cell lymphomas.