SYNTHETIC-LETHAL PHARMACOLOGICAL INTERACTIONS IN MYC-DRIVEN LYMPHOMAS: A ROLE FOR GLUCOCORTICOIDS IN TARGETED THERAPY

Diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma, includes aggressive subtypes that remain difficult to treat. One of the molecular features associated with poor prognosis is the presence of chromosomal translocations that activate the MYC oncogene, in particular when associated with concurrent activation of BCL2, which leads to an aggressive disease subtype commonly known as double-hit lymphomas (DHL). Since direct targeting of MYC remains challenging, we sought to unravel synthetic-lethal vulnerabilities as alternative therapeutic options against MYC-driven tumors. Toward this aim, we performed an unbiased high-throughput pharmacological screen in a murine B-lymphoid cell line with conditional MYC activation and identified a set of compounds that preferential kill MYC-overexpressing cells. Unexpectedly, these included glucocorticoids (GCs) with Budesonide scoring as the top candidate. Targeted experiments confirmed that MYC also sensitizes B-cells to another GC, Prednisolone, the active metabolite of Prednisone, itself an integral component of the frontline therapeutic regimen R-CHOP. Functional assays revealed that MYC activation markedly sensitizes B cells to GC-induced apoptosis through the intrinsic mitochondrial pathway. Transcriptomic profiling confirmed that MYC differentially modulates the transcriptional response to GCs, reinforcing the activation of stress and apoptotic programs while attenuating the repression of proliferative and metabolic genes, thus providing a mechanistic basis for MYC-specific cytotoxicity. Guided by these findings, we uncovered a strong synergy between GCs and the selective BCL2 inhibitor Venetoclax (ABT199) in killing a human DHL cell line, providing a rationale for combining these drugs against this aggressive lymphoma subtype. Additional combinatorial experiments showed that Prednisolone contributes to the cytotoxicity of the pharmacological CHOP backbone in MYC-overexpressing B-cells. Collectively, our data identify GCs as potent MYC-synthetic lethal agents, mechanistically linked to MYC-driven remodeling of GC-regulated transcription, revealing an unexpected mechanism of action for these long-standing therapeutic agents.