Characterization and targeting of rapid nucleotide exchange RAS mutations

RAS突变驱动了大部分致命的人类肿瘤，但没有靶向治疗 进了诊所。我们和其他人已经表明，某些致癌RAS突变具有独特的 生物化学性质，并已显示RAS突变的功能类别受到差异调节， 为RAS等位基因定制治疗方法打开了大门。RAS等位基因特异性治疗具有潜力 对于快速临床翻译，这是值得的，因为（1）RAS突变状态已经是常规的 在当前临床实践中评估了多种常见癌症，（2）有效和选择性小分子 靶向RAS信号通路的成员或那些成员的调节剂已经可用，以及（3） RAS突变在癌症中发生得足够频繁，以至于即使在癌症患者中， 尽管治疗适用于RAS突变阳性肿瘤的子集。这项建议旨在发展直接和 间接治疗策略的基础上的独特模式的激活和由此产生的信号性质的 KRAS A146T和其他RAS交换突变体。这项研究具有转化治疗的意义， KRAS A146 T已经在临床实践中进行了筛选，但目前还没有靶向治疗。

RAS mutations drive a large proportion of deadly human tumors but no targeted therapies have advanced to clinic. We and others have shown that certain oncogenic RAS mutations have unique biochemical properties and have shown that functional classes of RAS mutations are differentially regulated, opening the door to RAS allele-tailored treatment approaches. RAS allele-specific therapies have the potential for rapid clinical translation and would be worthwhile because (1) RAS mutation status is already routinely assessed in current clinical practice for multiple common cancers, (2) potent and selective small molecules targeting members of RAS signaling pathways, or regulators of those members are already available, and (3) RAS mutations occur frequently enough in cancer that a significant number of patients would benefit even though therapies apply to subsets of RAS mutation-positive tumors. This proposal seeks to develop direct and indirect therapeutic strategies based on the unique mode of activation and resultant signaling properties of KRAS A146T and other RAS exchange mutants. This study has translational therapy implications given that KRAS A146T is already screened for in clinical practice, but no targeted therapies currently exist.