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Preventing adaptive drug resistance through Mediator kinase inhibition

通过抑制介体激酶来预防适应性耐药性

基本信息

批准号：
10668528
负责人：
Eugenia V Broude
金额：
$ 59.69万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668528
关键词：
Affect Antineoplastic Agents Breast Cancer cell line Breast Carcinoma Cell Line Cells Derivation procedure Development Drug Targeting Drug resistance ERBB2 gene Epithelium Exposure to Gene Expression Genetic Transcription Genomics Growth Heterogeneity Human Human Cell Line Immune Immune system Immunocompetent Immunodeficient Mouse Immunologic Deficiency Syndromes In Vitro Malignant Epithelial Cell Mediator Mesenchymal MicroRNAs Mouse Mammary Tumor Virus Mus Mutagenesis Neoplasm Metastasis Paclitaxel Pathway interactions Patient-derived xenograft models of breast cancer Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphorylation Phosphotransferases Population Prevention Process Property Protein Isoforms Protein Kinase Remission Induction Resistance Resistance development Role Signal Transduction Signal Transduction Pathway Stromal Cells Testing Treatment outcome Tumor Promotion Xenograft procedure acquired drug resistance cancer drug resistance cancer stem cell cancer therapy clinical development clinically relevant exome sequencing gene induction genetically modified cells in vivo inhibitor inhibitor therapy kinase inhibitor lapatinib malignant breast neoplasm miRNA expression profiling mouse model mutant neoplastic cell non-genetic novel novel drug class novel therapeutics patient derived xenograft model pharmacologic pre-clinical prevent programs prototype single-cell RNA sequencing therapy development therapy resistant transcription factor transcriptional reprogramming transcriptome sequencing transcriptomics tumor tumor growth tumor initiation tumor progression tumor xenograft

项目摘要

Cancer drug resistance is driven in part by the plasticity of tumor cells that allows for therapy-induced adaptation of their transcriptional program. This adaptive drug resistance is associated with the acquisition of various phenotypic changes that promote tumor growth, metastasis and resistance to other therapies. Experimental drugs targeting CDK8/19 Mediator kinase that regulates transcriptional reprogramming were found to suppress the development of resistance to different classes of targeted and conventional anticancer agents. We hypothesize that the emergence of adaptive drug resistance in vitro and in vivo, with concurrent acquisition of tumor-promoting phenotypes, can be prevented by inhibiting Mediator kinase. We will test this hypothesis in HER2-positive breast cancers by analyzing the effects of Mediator kinase inhibition on the emergence of resistance to a HER2-targeting drug (lapatinib) and a conventional drug (paclitaxel). We will pursue the following Specific Aims. (1) The effect of Mediator kinase deficiency on the development of adaptive drug resistance in vitro will be analyzed by generating derivatives of HER2-positive human breast cancer cell lines that will express wild-type or kinase-dead Mediator kinase and by analyzing the effects of Mediator kinase mutagenesis or treatment with selective CDK8/19 inhibitors on the emergence of adaptive resistance to lapatinib or paclitaxel. Comprehensive phenotypic, genomic and transcriptomic analyses will be used to evaluate the effect of drug adaptation and Mediator kinase inhibition on the acquisition of tumor-promoting phenotypes and to identify signal transduction pathways, inhibitors of which could be combined with CDK8/19 inhibitors to enhance the prevention of resistance. (2) HER2-positive human cell lines with different Mediator kinase status and a panel of HER2- positive breast cancer patient-derived xenografts (PDX) will be selected for lapatinib and paclitaxel resistance in vivo, to compare the resistance-preventing effects of Mediator kinase deficiency in tumor cells alone and with the effects of its pharmacological inhibition in both tumor and stromal cells. Transcriptomic and phenotypic analysis will be used to delineate the effects of drug selection and Mediator kinase inhibition on gene expression in tumor and stromal cells. Whole exome sequencing of PDX tumors will reveal if Mediator kinase inhibition prevents the emergence of new drug-resistant tumor lineages or suppresses the growth of drug-resistant cells that may pre-exist in heterogeneous PDXs. (3) The effects of Mediator kinase on the emergence of drug resistance will also be investigated in a murine Her2/Neu-driven mouse mammary carcinoma cells adapted for syngeneic growth, both in vitro (as in Aim 1) and in vivo using both immunocompetent and immunodeficient hosts. This analysis will elucidate the effect of the host immune system on drug adaptation and the role of Mediator kinase in this effect. The proposed program will delineate the roles of Mediator kinase in tumor adaptation to treatment, in vitro and in vivo, and will indicate whether Mediator kinase-inhibiting drugs may be able to extend the duration of remission induced by cancer therapy.

癌症耐药性部分是由肿瘤细胞的可塑性驱动的，这种可塑性允许治疗诱导的适应