Targeting Hyperactive Ras Signaling in Pediatric Cancer.

IF 7.8 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor perspectives in medicine Pub Date : 2024-07-15 DOI:10.1101/cshperspect.a041572
Anya Levinson, Kevin Shannon, Benjamin J Huang
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Abstract

Somatic RAS mutations are among the most frequent drivers in pediatric and adult cancers. Somatic KRAS, NRAS, and HRAS mutations exhibit distinct tissue-specific predilections. Germline NF1 and RAS mutations in children with neurofibromatosis type 1 and other RASopathy developmental disorders have provided new insights into Ras biology. In many cases, these germline mutations are associated with increased cancer risk. Promising targeted therapeutic strategies for pediatric cancers and neoplasms with NF1 or RAS mutations include inhibition of downstream Ras effector pathways, directly inhibiting the signal output of oncogenic Ras proteins and associated pathway members, and therapeutically targeting Ras posttranslational modifications and intracellular trafficking. Acquired drug resistance to targeted drugs remains a significant challenge but, increasingly, rational drug combination approaches have shown promise in overcoming resistance. Developing predictive preclinical models of childhood cancers for drug testing is a high priority for the field of pediatric oncology.

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靶向小儿癌症中亢进的 Ras 信号
体细胞RAS突变是儿童和成人癌症中最常见的驱动因素之一。体细胞KRAS、NRAS和HRAS突变具有不同的组织特异性。1 型神经纤维瘤病和其他 RAS 病发育障碍患儿的种系 NF1 和 RAS 突变为 Ras 生物学提供了新的见解。在许多情况下,这些种系突变与癌症风险增加有关。针对有 NF1 或 RAS 突变的儿科癌症和肿瘤的有希望的靶向治疗策略包括抑制下游 Ras 效应通路、直接抑制致癌 Ras 蛋白和相关通路成员的信号输出,以及针对 Ras 翻译后修饰和细胞内贩运的治疗。靶向药物的获得性耐药性仍然是一项重大挑战,但越来越多的合理联合用药方法已显示出克服耐药性的希望。开发用于药物测试的预测性儿童癌症临床前模型是儿科肿瘤学领域的当务之急。
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来源期刊
Cold Spring Harbor perspectives in medicine
Cold Spring Harbor perspectives in medicine MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
14.30
自引率
1.90%
发文量
44
审稿时长
4-8 weeks
期刊介绍: Cold Spring Harbor Perspectives in Medicine is a monthly online publication comprising reviews on different aspects of a variety of diseases, covering everything from the molecular and cellular bases of disease to translational medicine and new therapeutic strategies. Cold Spring Harbor Perspectives in Medicine is thus unmatched in its depth of coverage and represents an essential source where readers can find informed surveys and critical discussion of advances in molecular medicine.
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