Integrative profiling strategies to guide personalized therapy in mantle cell lymphoma: a pilot study

Mantle cell lymphoma (MCL) responds to frontline therapy but is susceptible to relapse. While Bruton's tyrosine kinase inhibitors (BTKi) achieve high response rates, most patients eventually experience disease progression. Predicting responses to subsequent treatments remains challenging due to the lack of an established platform. Heterogeneity in gene alterations and cellular pathways contribute to resistance, complicating treatment approaches. Here, we present a multi-modal profiling platform, targeting key pathways rather than focusing on singular DNA-associated lesions. We identified dysregulated signaling pathways by performing gene expression profiling on 20 MCL samples using a custom MCL MATCH gene set and analyzed the data with gene-set variation analysis. We also screened 22 therapeutics in vitro to assess their efficacy. Whole exome sequencing was conducted to identify prevalent and actionable mutations linked to enriched pathways. Finally, we tested selected therapeutics in patient-derived xenograft mouse models to predict potential response in corresponding patients. Based on our integrative profiling, we identified the top therapeutic candidates for three patients in this study. This integrative platform may help identify targeted therapies for BTKi-relapsed/refractory MCL patients in clinical settings.