Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell Lymphoma

Simple Summary Diffuse large B-cell lymphoma (DLBCL) is an aggressive blood cancer and the most common non-Hodgkin lymphoma. DLBCL has a 40% relapse rate with current therapies, warranting investigations into potential vulnerabilities leading to new treatment avenues. Many DLBCLs increase the levels of a protein called BCL2 that blocks lymphoma cell death and contributes to treatment resistance and relapse. A drug was developed to target BCL2 (venetoclax/ABT-199) to induce DLBCL cell death. However, it was ineffective as a single agent, revealing that DLBCL relies on more than BCL2 for survival. Our study of intrinsic venetoclax resistance and developed venetoclax resistance in DLBCL identifies new targetable vulnerabilities in DLBCL by exposing dependencies on critical cellular processes. Our findings have the potential to lead to new treatments for DLBCL and possibly other B-cell lymphomas.Abstract Clinical trials with single-agent venetoclax/ABT-199 (anti-apoptotic BCL2 inhibitor) revealed that diffuse large B-cell lymphoma (DLBCL) is not solely dependent on BCL2 for survival. Gaining insight into pathways/proteins that increase venetoclax sensitivity or unique vulnerabilities in venetoclax-resistant DLBCL would provide new potential treatment avenues. Therefore, we generated acquired venetoclax-resistant DLBCL cells and evaluated these together with intrinsically venetoclax-resistant and -sensitive DLBCL lines. We identified resistance mechanisms, including alterations in BCL2 family members that differed between intrinsic and acquired venetoclax resistance and increased dependencies on specific pathways. Although combination treatments with BCL2 family member inhibitors may overcome venetoclax resistance, RNA-sequencing and drug/compound screens revealed that venetoclax-resistant DLBCL cells, including those with TP53 mutation, had a preferential dependency on oxidative phosphorylation. Mitochondrial electron transport chain complex I inhibition induced venetoclax-resistant, but not venetoclax-sensitive, DLBCL cell death. Inhibition of IDH2 (mitochondrial redox regulator) synergistically overcame venetoclax resistance. Additionally, both acquired and intrinsic venetoclax-resistant DLBCL cells were similarly sensitive to inhibitors of transcription, B-cell receptor signaling, and class I histone deacetylases. These approaches were also effective in DLBCL, follicular, and marginal zone lymphoma patient samples. Our results reveal there are multiple ways to circumvent or overcome the diverse venetoclax resistance mechanisms in DLBCL and other B-cell lymphomas and identify critical targetable pathways for future clinical investigations.