Cancer kinomics: Kinome-wide analysis of drug-resistance mechanisms in human cancers

总结：西北地区患癌症的比例不成比例。我们将探索使从人类患者样本中获得的癌细胞能够长期暴露于蛋白激酶抑制剂的机制，这是个性化癌症治疗的关键临床武器。这是一个战略性的行业：学术博士合作伙伴关系，由2016年利物浦大学MRC接近发现奖"泵启动"，这使我们能够产生重要的初步发现。这些数据证实，细胞群产生耐药性的激酶抑制剂治疗的患者表现出独特的遗传特征，不同于那些在急性给药的患者，他们的鉴定提供了一个令人兴奋的新的机会，靶向机制的耐药性在癌症patient.Background：长期治疗的癌细胞激酶抑制剂导致转录“重新布线”的激酶信号网络。这种途径的"进化"可以通过基于nanoString的mRNA激酶组分析和蛋白质组学来分析，这是我们在利物浦开发的用于个性化癌细胞分析的定量技术。通过最近与MRC-PPUU（邓迪大学）的合作，我们已经确定在激酶抑制剂暴露的急性和长期条件下，不同的蛋白激酶mRNA被上调，并且可以替代药物抑制的途径（巴戈等人，2016，EMBO J. 35，9802）。这一发现对于决定如何以及何时对分层患者进行联合治疗具有重要意义。缺少的是对患者特异性癌症中发现的mRNA和蛋白质组激酶特征及其在肿瘤学中的预后或诊断潜力的理解。这个MRC DiMeN博士研究生支持一个既定的合作网络，并包括与阿斯利康学术环境之外的技能培训。这个成功的制药团队为治疗转移性非小细胞肺癌的Tagrisso/Omisertinib的开发做出了贡献，这是2016年从试验到监管批准最快获得批准的蛋白激酶抑制剂。学生工作包：我们将评估临床相关癌细胞组中发现的临床激酶抑制剂挑战的反应和耐药"特征"。这些患者来源的细胞是阿斯利康独特的一部分。从我们的行业和学术合作伙伴关系产生的数据将告知全激酶组分析如何用于个体患者的优势。具体而言，它有可能增加靶向治疗各种人类癌症中耐药持续者的治疗潜力。总体博士研究生成果可能包括：1）为博士生提供学术和非学术环境中的协作研究培训，这些环境具有分层医学卓越但具有不同的技术优势。包括在AZ约3个月的实习，以最大限度地提高通用和可转移的技能。2)加强DiMeN大学之间的合作，并帮助将利物浦定位为基于激酶组的药物治疗肿瘤样本筛选的卓越培训中心。3）约50个已知基因组和药物反应性的患者来源癌细胞系中临床化合物的全激酶组表达数据。4)全激酶组动力学，以及在i）急性和ii）在已知靶点接合的浓度下延长化合物暴露后临床化合物的选定磷酸蛋白质组学。5）针对消除或致敏对次级疗法（包括针对小分子的抗体疗法或组合）具有抗性的群体的药物筛选AZ和商业药物文库。

Summary:The North West suffers disproportionately from cancer-associated morbity. We will explore mechanisms that enable cancer cells obtained from human patient samples to survive prolonged exposure to protein kinase inhibitors, key clinical weapons for personalized cancer therapy. This is a strategic Industry:Academic PhD partnership that was ""pump-primed"" by a 2016 University of Liverpool MRC Proximity to Discovery Award, which allowed us to generate important preliminary findings. These data confirm that cell populations that generate drug-resistance in patients treated with kinase inhibitors exhibit unique genetic profiles distinct from those in acutely-dosed patients, and their identification provides an exciting new opportunity for targetting mechanisms of drug-resistance in cancer patients.Background:Prolonged treatment of cancer cells with kinase inhibitors leads to transcriptional 're-wiring' of kinase signalling networks. This pathway 'evolution' can be analysed by nanoString-based mRNA kinome profiling and proteomics, quantitative technologies we are developing in Liverpool for personalized cancer cell profiling. Through a recent collaboration with the MRC-PPUU (University of Dundee), we have established that under acute and prolonged conditions of kinase inhibitor exposure, different protein kinase mRNAs are upregulated, and that one can substitute for drug-inhibited pathways (Bago et al., 2016, EMBO J. 35, 9802). This finding has significant consequences for deciding how, and when, combinations of therapeutics should be given to stratified patients. What is missing is understanding of the mRNA and proteomic kinase signatures found in patient-specific cancers, and its prognostic or diagnostic potential in oncology. This MRC DiMeN PhD studentship supports an established collaborative network, and includes skill-set training outside the academic environment with AstraZeneca. This successful pharmaceutical team contributed to the development of Tagrisso/Omisertinib for metastatic non-small cell lung cancer, the fastest protein kinase inhibitor to receive approval in terms of passage from trials to its regulatory approval in 2016.Studentship work package:We will evaluate response and resistance 'signatures' found in clinically-relevant cancer cell panels challenged with clinical kinase inhibitors. These patient-derived cells are part of a unique AstraZeneca panel. Data produced from our Industry and academic partnership will inform how whole-kinome analysis can be used to individual patients' advantage. Specifically, it has the potential to increase the therapeutic potential of targeting drug-resistant persistors in various human cancers.Overall PhD studentship outcomes could include:1) Provide PhD student(s) with collaborative research training in academic and non-academic settings of stratified medicine excellence but with different technological strengths. To include ~3 months placement at AZ to maximize generic and transferable skills. 2) Strengthen collaborations between DiMeN Universities and help position Liverpool as a training centre of excellence for kinome-based screening of drug-treated tumour samples.3) Whole kinome expression data for clinical compounds in ~50 patient-derived cancer cell lines of known genomic and drug-responsiveness. 4) Whole kinome dynamics, and selected phosphoproteomics for clinical compounds after i) acute and ii) prolonged compound exposure at a concentration where target engagement is known.5) Screening of AZ and commercial drug libraries for drugs that eliminate, or sensitise, populations resistant to secondary therapies, including antibody therapies to small molecules, or combinations.