K-Ras mutant-specific vulnerabilities for novel pancreatic cancer therapies

新型胰腺癌疗法的 K-Ras 突变体特异性漏洞

基本信息

批准号：
9204655
负责人：
Guy Aaron Hobbs
金额：
$ 5.71万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9204655
关键词：
Address Affect Affinity Amino Acids Anchorage-Independent Growth Animals Apoptosis Binding Biochemical Biology Cancer Biology Cancer Model Cell Aging Cell Culture Techniques Cell model Cells Cellular biology Clinic Clinical Colon Carcinoma Communities Data Dependence Development Disease Drug Targeting Employee Strikes Epidermal Growth Factor Receptor Exhibits Failure Family Foundations Frequencies GTP Binding Growth Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases HRAS gene Human Immune In Vitro KRAS2 gene Kinetics Maintenance Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Missense Mutation Mus Mutate Mutation Nucleotides Oncogenes Oncogenic Outcome Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic duct Pathway interactions Patients Perception Pharmacology Phosphorylation Preclinical Drug Evaluation Property Protein Biochemistry Protein Isoforms Protein Kinase Protein Region Proteins RAS genes Regulation Role Scientist Signal Induction Signal Transduction Specificity Structure Survival Rate System Testing Therapeutic Tissues Training Treatment Efficacy Tumorigenicity X-Ray Crystallography ataxia telangiectasia mutated protein base cancer therapy cancer type design drug discovery inhibitor/antagonist insight matrigel melanoma mouse model mutant mutational status new therapeutic target next generation novel preference protein structure public health relevance ras Proteins small molecule targeted treatment tumor tumor growth tumor initiation tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Despite more than three decades of intense efforts, no clinically effective therapeutic strategies have been developed targeting the KRAS oncogene, which is mutationally activated in >95% of pancreatic ductal adenocarcinoma (PDAC). One reason for this failure has been the perception that "all KRAS mutations are created equal", with most anti-KRAS strategies based on the development of a pan-mutant KRAS inhibitor. There are 134 different missense mutations identified in KRAS in all cancers, with 98% found at one of three hotspots, amino acids G12, G13 or Q61. The recent provocative identification of a small molecule antagonist specific for one mutant, KRAS G12C, has begun to shift the paradigm, supporting the concept that mutation- selective therapeutic approaches may be a more effective strategy. Building on this paradigm, this proposal focuses on two specific KRAS mutations. Aim 1 will determine whether KRAS G12R differentially activates effector signaling compared with the more commonly seen and studied G12D/V/C mutations found in ~70% of all cancers. While KRAS G12R is rare in all cancers (3%), this mutation is the third most common KRAS mutant found in PDAC. As structural analyses found that the G12R mutation, but not G12D/V/C mutations, was altered in a region of the protein critical for effector recognition, it is likely that this mutant has altered downstream effector signaling. Further supporting this possibility is the fact that PDAC patients with G12R mutations had a significantly better overall survival (15.6 months) relative to patients with non-G12R mutations (8.9 months). Consequently, KRAS G12R mutant PDAC may be uniquely susceptible to a distinct effector- targeted therapeutic strategy. Aim 2 focuses on G13 mutations, poorly studied and the least understood mutation hotspot compared with G12 and Q61 mutations. Although G13D is the third most common KRAS mutation in all cancers (13%), it is rarely observed in PDAC (<1%). The G13D mutation causes a biochemically distinct alteration not seen with G12 mutations; thus, G13D mutations may require a distinct therapeutic approach than G12 mutant cancers. Although eight different KRAS missense mutations are found at G13, G13D comprises the vast majority (90%). In contrast, the G13D mutation is rarely seen in the highly related HRAS isoform (4%), with G13R the predominant G13 mutation in HRAS (81%), yet rare in KRAS (1%). Taken together, these striking frequency differences argue that cancer type and RAS isoform-distinct differences in the oncogenic potency of the G13D mutation may exist. Using a human pancreatic cell model, this study will apply kinome-wide protein kinase and phosphorylation profiling together with a mouse model of pancreatic cancer to assess tumorigenic and metastatic growth. In summary, this study will identify KRAS mutation- specific effector signaling that can then be exploited for the design of mutation-selective effector signaling- targeted therapeutic strategies for pancreatic cancer, a disease with no effective therapeutic options and a dismal 5-year survival rate of 6%.

描述（由适用提供）：尽管有超过三十年的激烈努力，但尚未开发出针对KRAS癌基因的临床有效的治疗策略，KRAS癌基因在胰腺导管腺癌（PDAC）> 95％> 95％均被突变激活。造成这种失败的原因之一是人们认为“所有KRAS突变都是平等的”，大多数反KRAS策略基于Pan-Mutant Kras抑制剂的发展。在所有癌症中，KRAS中都有134个不同的错义突变，在三个热点之一，氨基酸G12，G13或Q61中发现了98％。最近针对一个突变体Kras G12c的小分子拮抗剂的挑衅性鉴定已经开始改变范式，支持突变选择性治疗方法可能是更有效的策略的概念。在此范式的基础上，该提案着重于两个特定的KRAS突变。 AIM 1将确定KRAS G12R是否与更常见和研究的G12D/V/C突变相比，在所有癌症中发现了效应子信号传导是否不同。尽管KRAS G12R在所有癌症中很少见（3％），但该突变是PDAC中发现的第三大常见的KRAS突变体。正如结构分析发现，在效应子识别至关重要的蛋白质区域中，G12R突变（而不是G12D/V/C突变）改变了，这种突变体可能改变了下游效应子信号传导。进一步支持这种可能性的是，与非G12R突变患者相比，具有G12R突变的PDAC患者的总生存期（15.6个月）明显更好（8.9个月）。因此，KRAS G12R突变体PDAC可能独特地容易受到明显的靶向靶向治疗策略的影响。 AIM 2专注于G13突变，与G12和Q61突变相比，研究较少，而理解的突变热点最少。尽管G13D是所有癌症中第三大常见的KRAS突变（13％），但在PDAC中很少观察到它（<1％）。 G13D突变会引起G12突变未见的生化不同的改变。因此，与G12突变癌相比，G13D突变可能需要独特的治疗方法。尽管在G13上发现了八个不同的KRAS错义突变，但G13D建立了绝大多数（90％）。相反，在高度相关的HRA同工型（4％）中，G13D突变很少见，而G13R在HRAS中是主要的G13突变（81％），但在KRAS中很少见（1％）。综上所述，这些引人注目的频率差异表明，可能存在癌症类型和RAS同工型在G13D突变的致癌效力中的差异。使用人类胰腺细胞模型，本研究将采用全部范围的蛋白激酶和磷酸化分析以及胰腺癌的小鼠模型来评估致瘤性和转移性生长。总而言之，这项研究将确定KRAS突变 - 特异性效应子信号传导，然后可以探索，以设计突变选择性效应子信号传导针对胰腺癌的治疗策略，这种疾病没有有效的治疗选择和惨淡的5年生存率6％。