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

• 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
• 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

 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（由申请人提供）：尽管经过三十多年的努力，尚未开发出靶向KRAS癌基因的临床有效的治疗策略，KRAS癌基因在>95%的胰腺导管腺癌（PDAC）中突变激活。这种失败的一个原因是“所有KRAS突变都是平等的”，大多数抗KRAS策略都是基于泛突变KRAS抑制剂的开发。在所有癌症的KRAS中发现了134种不同的错义突变，其中98%发现于三个热点之一，氨基酸G12，G13或Q61。最近对一种突变体KRAS G12 C特异性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。基于这一范式，该建议侧重于两个特定的KRAS突变。目的1将确定KRAS G12 R是否与在约70%的所有癌症中发现的更常见和研究的G12 D/V/C突变相比差异激活效应信号传导。虽然KRAS G12 R在所有癌症中很少见（3%），但该突变是PDAC中发现的第三常见KRAS突变。由于结构分析发现G12 R突变而非G12 D/V/C突变在对效应子识别至关重要的蛋白质区域中发生改变，因此该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事实是，G12 R突变的PDAC患者的总生存期（15.6个月）明显优于非G12 R突变的患者（8.9个月）。因此，KRAS G12 R突变体PDAC可能对独特的效应子靶向治疗策略特别敏感。目的2关注G13突变，与G12和Q61突变相比，G13突变研究较少，也是最不了解的突变热点。虽然G13 D是所有癌症中第三常见的KRAS突变（13%），但在PDAC中很少观察到（<1%）。G13 D突变引起G12突变所未见的生物化学上的独特改变;因此，G13 D突变可能需要与G12突变癌症不同的治疗方法。虽然在G13发现了8种不同的KRAS错义突变，但G13 D占绝大多数（90%）。相比之下，G13 D突变在高度相关的HRAS亚型中罕见（4%），G13 R是HRAS中主要的G13突变（81%），但在KRAS中罕见（1%）。总之，这些惊人的频率差异表明，癌症类型和RAS亚型在G13 D突变的致癌效力上可能存在明显差异。使用人胰腺细胞模型，本研究将应用全激酶组蛋白激酶和磷酸化谱与胰腺癌小鼠模型一起评估致瘤性和转移性生长。总之，本研究将鉴定KRAS突变特异性效应子信号传导，然后可以利用其设计胰腺癌的突变选择性效应子信号传导靶向治疗策略，胰腺癌是一种没有有效治疗选择的疾病，5年生存率为6%。