Project description:Ibrutinib, a bruton's tyrosine kinase inhibitor, was shown to have high response rates in mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. However, emergence of ibrutinib resistance (IR) and subsequent fatal progression is of significant clinical concern. By implementing genomics, chemical proteomics and drug screening, we report that enhancer remodeling-mediated transcriptional activation and adaptive signaling changes drive the malignant phenotype of IR. Accordingly, IR MCL cells are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 9 (CDK9). Thus, targeting transcriptional activation offers a novel strategy to prevent the emergence of IR and overcome IR via impeding IR-associated cellular signaling reprogramming in MCL. In addition, our ex-vivo microfluidic image-based functional drug screen can function not only as new technology platforms for predicting clinical therapeutic response but also, in conjunction with genomic profiling in primary MCL samples, identify the molecular vulnerabilities for drug resistance evolution, providing insight into the underlying IR mechanisms for MCL and other B-cell malignancies
Project description:Ibrutinib, a bruton's tyrosine kinase inhibitor, was shown to have high response rates in mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. However, emergence of ibrutinib resistance (IR) and subsequent fatal progression is of significant clinical concern. By implementing genomics, chemical proteomics and drug screening, we report that enhancer remodeling-mediated transcriptional activation and adaptive signaling changes drive the malignant phenotype of IR. Accordingly, IR MCL cells are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 9 (CDK9). Thus, targeting transcriptional activation offers a novel strategy to prevent the emergence of IR and overcome IR via impeding IR-associated cellular signaling reprogramming in MCL. In addition, our ex-vivo microfluidic image-based functional drug screen can function not only as new technology platforms for predicting clinical therapeutic response but also, in conjunction with genomic profiling in primary MCL samples, identify the molecular vulnerabilities for drug resistance evolution, providing insight into the underlying IR mechanisms for MCL and other B-cell malignancies
Project description:Ibrutinib, a bruton's tyrosine kinase inhibitor, was shown to have high response rates in mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. However, emergence of ibrutinib resistance (IR) and subsequent fatal progression is of significant clinical concern. By implementing genomics, chemical proteomics and drug screening, we report that enhancer remodeling-mediated transcriptional activation and adaptive signaling changes drive the malignant phenotype of IR. Accordingly, IR MCL cells are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 9 (CDK9). Thus, targeting transcriptional activation offers a novel strategy to prevent the emergence of IR and overcome IR via impeding IR-associated cellular signaling reprogramming in MCL. In addition, our ex-vivo microfluidic image-based functional drug screen can function not only as new technology platforms for predicting clinical therapeutic response but also, in conjunction with genomic profiling in primary MCL samples, identify the molecular vulnerabilities for drug resistance evolution, providing insight into the underlying IR mechanisms for MCL and other B-cell malignancies
