Dysregulation of Transcription Machinery Drives the Acquisition of BTK Inhibitor and Venetoclax Treatment Resistance in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is an incurable B-cell malignancy with current front-line treatment regimens. Dysregulated B-cell receptor signaling and resistance to apoptosis are major hallmarks in MCL pathobiology. Bruton's tyrosine kinase inhibitors (BTKi), such as ibrutinib, and BCL-2 inhibitors, such as venetoclax, have been used to treat refractory and relapsed (R/R) MCL. While these agents show clinical efficacy, patients frequently develop drug resistance with consequent poor clinical outcomes. We previously characterized the molecular mechanisms of drug response and resistance to BTKi and venetoclax single-agent therapies in MCL and identified the combination of BTKi and venetoclax as a novel approach for overcoming drug resistance and providing a more durable and synergistic response in MCL. Translation of our preclinical model was achieved through the establishment of a randomized multicenter phase 3 clinical trial with BTKi-venetoclax vs BTKi-placebo. Although this trial showed improved responses to BTKi-venetoclax therapy, the majority of patients ultimately developed resistance to this regimen. Thus, there is an urgent need to identify new therapeutic targets and to develop newer therapeutic agents and strategies to overcome and prevent the emergence of therapy resistance. With the goal of eradicating residual resistant tumor subclones and sustaining complete remissions, we here characterize the molecular genetic and epigenetic resistance mechanisms to BTKi-venetoclax combination therapy using multi-omics approaches including scRNA-seq and scATAC-seq in MCL. Our integrative multi-omics single-cell analysis reveals that epigenetic chromatin accessibility alterations underpin BTKi-venetoclax combination treatment resistance-associated transcriptome reprogramming and resistance evolution. We also validate the functional role of epigenetic regulation and transcription activation determinants (CDK7, CDK9) in BTKi-venetoclax resistance evolution. Furthermore, we establish that BTKi-venetoclax treatment reshapes the tumor microenvironment (TME) in MCL in favor of immune-responsiveness, which is evidenced by an enhanced susceptibility to immunotherapy. Taken together, this work demonstrates that the adaptive transcriptional machinery activation and immune-responsive TME state transition induced by BTKi-venetoclax are therapeutic vulnerabilities that may be effectively exploited by both targeted- (e.g., CDK9 inhibitors) and immune-therapies (e.g., CD19 CAR-T) to overcome MCL therapy resistance. This highly translational work has the potential to have an immediate impact on MCL treatment approaches through the rational design of new combination regimens.

Craig:Bayer: Consultancy, Other: Expert Testimony; BeiGene: Honoraria. Shah:AstraZeneca: Consultancy; Bristol Myers Squibb: Consultancy; Jazz Pharmaceuticals: Consultancy; Eli Lilly: Consultancy; Amgen: Consultancy; Kite Pharma: Consultancy; Adaptive Biotechnologies: Consultancy; Autolus, Beigene, Century Therapeutics, Deciphera, Jazz, Kite/Gilead, Pfizer, Precision Biosciences, Novartis, Takeda: Consultancy; Jazz Pharmaceuticals, Kite-Gilead, Servier: Research Funding; Pepromene Bio: Other: DSMB. Portell:Merck: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy; Prelude: Research Funding; SeaGen/Pfizer: Research Funding; Infinity: Research Funding; Genentech/Roche: Research Funding; Kite: Research Funding. Williams:AbbVie: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy; Janssen: Research Funding.