Mechanisms of Resistance to Targeted Therapy最新文献

{"title":"Abstract IA23: Enhancer remodeling in response to MEK inhibition in TNBC","authors":"J. Zawistowski, Samantha M. Bevill, G. Johnson","doi":"10.1158/1557-3125.ADVBC17-IA23","DOIUrl":"https://doi.org/10.1158/1557-3125.ADVBC17-IA23","url":null,"abstract":"In contrast to acquired resistance to targeted therapeutics via genomic changes, adaptive resistance in cancer involves rapid cellular reprogramming at a nongenomic level. In triple-negative breast cancer (TNBC) a robust transcriptional adaptation to MEK inhibition (MEKi) by the MEK inhibitor, trametinib, is observed in both TNBC patients and preclinical models. This transcriptional adaptation includes upregulation of bypass signaling molecules, including receptor tyrosine kinases (RTKs), to reactivate cellular proliferation programs in the presence of the initial drug challenge. Rather than attempting to antagonize RTK upregulation using a secondary kinase inhibitor in conjunction with the initial, primary targeted therapeutic, we have employed a strategy to broadly inhibit MEKi-induced transcriptional adaptation through the use of BET bromodomain inhibitors. BET protein family bromodomains bind to acetylated lysine moieties of histone subunits or transcription factors to regulate transcriptional elongation via recruitment of P-TEFb, a RNA polymerase II regulatory complex containing CDK9 and Cyclin T1. In TNBC we found the combination of MEKi + BET bromodomain inhibition (BETi) resulted in durable tumor cell growth inhibition not obtained with trametinib alone, nor with different kinase inhibitor combinations. Importantly, we observed in vivo MEKi + BETi synergy in orthotopic SUM159PT xenograft and T11 and 2225 mouse orthotopic syngeneic transplant models of TNBC. This synergism is not limited to TNBC, as we have shown that MEKi + BETi results in durable growth suppression in HER2+ breast cancer. A central question is the mechanism of BETi efficacy in the context of suppressing adaptation to targeted therapeutics. We asked if BRD4 function at enhancers is critical for adaptive transcription in response to MEK1/2 inhibition by trametinib. We found vast chromatin remodeling in the form of de novo enhancer formation and remodeling in response to trametinib in TNBC cells. Enhancers with pronounced BRD4 density and co-occupied with prototypical enhancer marks (H3K27ac, MED1, H3K4me1) were rapidly (1-4 h) formed genome-wide, including at sites proximal to receptor tyrosine kinase loci including DDR1, KDR, FGFR2, and PDGFRB, each influential in TNBC adaptive resistance. Trametinib-responsive enhancers were remodeled across the genome, but with BETi the total number of enhancers remained near baseline. In fact, BETi was able to disrupt enhancers seeded in response to trametinib. We observed correlation of transcriptional induction of genes proximal to the enhancer density induced by trametinib and a corresponding correlative decrease in transcript levels of the cognate genes of the seeded enhancers with combination MEKi+BETi treatment. Does the enhancer paradigm provide a potential source of pharmacologic targets for attenuating adaptive transcription beyond that of BRD4? In addition to BETi, we found that pharmacologic perturbation of CBP/p300 acetyltr","PeriodicalId":397189,"journal":{"name":"Mechanisms of Resistance to Targeted Therapy","volume":"6 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133091877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract IA22: Integrating immunotherapy and targeted therapy in breast cancer","authors":"Jean J. Zhao","doi":"10.1158/1557-3125.ADVBC17-IA22","DOIUrl":"https://doi.org/10.1158/1557-3125.ADVBC17-IA22","url":null,"abstract":"Therapeutic resistance is a major obstacle in the clinic for cancer treatment. Utilizing our novel genetically engineered mouse models (GEMMs) of cancer driven by inducible expression of oncogenic PIK3CA or HER2, coupled with pharmacologic approaches, we identified several significant resistance mechanisms to PI3K- or HER2-targeted therapy. For example, we found spontaneous focal amplification of Met and Myc, recurrent mutations in Ras and β-catenin, and compensatory activation of the MAPK pathway render resistance to PI3K inhibition. We recently identified Cyclin D1-CDK4 mediated resistance to HER2-targeted therapy through a signaling feedback loop. Beyond suppressing cell cycle progression, we found that CDK4/6 inhibitors promote antitumor immunity and increase cytotoxic T cell-mediated clearance of tumor cells, which is further enhanced by the addition of immune checkpoint blockade. More importantly, these results led to the design of clinical trials with CDK4/6 inhibitor in combination with HER2-targeted therapy and PD1 blockade for patients with metastatic, refractory HER2+ breast cancer. Parallel to GEMMs, we have led the efforts to establish and characterize novel cancer patient-derived xenograft (PDX) models, with an emphasis on brain metastases, an emerging clinical challenge. I will discuss how we have used these models to discover therapeutic strategies that integrate targeted therapy and immunotherapy to overcome resistance and to drive these discoveries to the clinical trials. Citation Format: Jean Zhao. Integrating immunotherapy and targeted therapy in breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA22.","PeriodicalId":397189,"journal":{"name":"Mechanisms of Resistance to Targeted Therapy","volume":"32 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127986698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}