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

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.