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

总结：西北地区患癌症相关疾病的比例过高。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（个性化癌症治疗的关键临床武器）的机制。这是一个战略性的产业：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，在接受激酶抑制剂治疗的患者中产生耐药的细胞群表现出与急性给药患者不同的独特遗传谱，它们的鉴定为癌症患者的靶向耐药机制提供了令人兴奋的新机会。背景：长期使用激酶抑制剂治疗癌细胞会导致激酶信号网络的转录“重新布线”。这种途径的“进化”可以通过基于纳米串的mRNA kinome分析和蛋白质组学来分析，我们正在利物浦开发用于个性化癌细胞分析的定量技术。通过最近与mrc - puu（邓迪大学）的合作，我们已经确定，在急性和长期暴露于激酶抑制剂的条件下，不同的蛋白激酶mrna上调，并且可以替代药物抑制途径（Bago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给予联合治疗具有重要意义。目前缺乏的是对患者特异性癌症中发现的mRNA和蛋白质组激酶特征的理解，以及它在肿瘤学中的预后或诊断潜力。这个MRC DiMeN博士奖学金支持一个已建立的合作网络，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年从试验到监管部门批准最快获得批准的蛋白激酶抑制剂。学生工作包：我们将评估与临床激酶抑制剂挑战的临床相关癌细胞组中发现的反应和耐药“特征”。这些患者来源的细胞是阿斯利康独特的小组的一部分。我们的行业和学术合作伙伴关系产生的数据将告知如何将全基因组分析用于个体患者的优势。具体来说，它有可能增加针对各种人类癌症的耐药持续存在的治疗潜力。博士研究生的总体成果可能包括：1)为博士研究生提供在学术和非学术环境下的合作研究培训，这些环境具有分层的医学优势，但具有不同的技术优势。包括在阿斯利康实习3个月，以最大限度地提高通用技能和可转移技能。2)加强迪门大学之间的合作，帮助利物浦成为基于kinome的药物治疗肿瘤样本筛选的卓越培训中心。3)约50种已知基因组和药物反应性的患者源性癌细胞系临床化合物的全基因组表达数据。4)临床化合物在已知靶标作用浓度下的急性和长期暴露后的全基因组动力学和选择的磷酸化蛋白质组学。5)筛选AZ和商业药物库，以消除或致敏对二级治疗（包括小分子抗体治疗或联合治疗）耐药的人群。

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.