Oncogenic activation of PI3KCA in cancers: Emerging targeted therapies in precision oncology

IF 6.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Genes & Diseases Pub Date : 2024-09-10 DOI:10.1016/j.gendis.2024.101430
Yuxiang Wang, Valery Rozen, Yiqing Zhao, Zhenghe Wang
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Abstract

Phosphoinositide 3-kinases (PI3Ks) are heterodimers consisting of a p110 catalytic subunit and a p85 regulatory subunit. The PIK3CA gene, which encodes the p110α, is the most frequently mutated oncogene in cancer. Oncogenic PIK3CA mutations activate the PI3K pathway, promote tumor initiation and development, and mediate resistance to anti-tumor treatments, making the mutant p110α an excellent target for cancer therapy. PIK3CA mutations occur in two hotspot regions: one in the helical domain and the other in the kinase domain. The PIK3CA helical and kinase domain mutations exert their oncogenic function through distinct mechanisms. For example, helical domain mutations of p110α gained direct interaction with insulin receptor substrate 1 (IRS-1) to activate the downstream signaling pathways. Moreover, p85β proteins disassociate from helical domain mutant p110α, translocate into the nucleus, and stabilize enhancer of zeste homolog 1/2 (EZH1/2). Due to the fundamental role of PI3Kα in tumor initiation and development, PI3Kα-specific inhibitors, represented by FDA-approved alpelisib, have developed rapidly in recent decades. However, side effects, including on-target side effects such as hyperglycemia, restrict the maximum dose and thus clinical efficacy of alpelisib. Therefore, developing p110α mutant-specific inhibitors to circumvent on-target side effects becomes a new direction for targeting PIK3CA mutant cancers. In this review, we briefly introduce the function of the PI3K pathway and discuss how PIK3CA mutations rewire cell signaling, metabolism, and tumor microenvironment, as well as therapeutic strategies under development to treat patients with tumors harboring a PIK3CA mutation.
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癌症中 PI3KCA 的致癌激活:精准肿瘤学中的新兴靶向疗法
磷酸肌醇 3 激酶(PI3K)是由 p110 催化亚基和 p85 调节亚基组成的异源二聚体。编码 p110α 的 PIK3CA 基因是癌症中最常发生突变的癌基因。致癌的 PIK3CA 基因突变会激活 PI3K 通路,促进肿瘤的发生和发展,并介导对抗肿瘤治疗的耐药性,从而使突变的 p110α 成为癌症治疗的绝佳靶点。PIK3CA 突变发生在两个热点区域:一个在螺旋结构域,另一个在激酶结构域。PIK3CA 螺旋结构域和激酶结构域突变通过不同的机制发挥致癌功能。例如,螺旋结构域突变的 p110α 可与胰岛素受体底物 1(IRS-1)直接相互作用,激活下游信号通路。此外,p85β蛋白与螺旋结构域突变的p110α脱离,转运到细胞核,并稳定泽斯特同源增强子1/2(EZH1/2)。由于 PI3Kα 在肿瘤发生和发展中的基础性作用,近几十年来,以美国 FDA 批准的 alpelisib 为代表的 PI3Kα 特异性抑制剂发展迅速。然而,包括高血糖等靶向副作用在内的副作用限制了阿来替尼的最大剂量,从而限制了其临床疗效。因此,开发 p110α 突变特异性抑制剂以规避靶向副作用成为靶向 PIK3CA 突变癌症的新方向。在这篇综述中,我们简要介绍了PI3K通路的功能,讨论了PIK3CA突变如何重新连接细胞信号传导、新陈代谢和肿瘤微环境,以及正在开发的治疗PIK3CA突变肿瘤患者的策略。
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来源期刊
Genes & Diseases
Genes & Diseases Multiple-
CiteScore
7.30
自引率
0.00%
发文量
347
审稿时长
49 days
期刊介绍: Genes & Diseases is an international journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch. Aims and Scopes Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis will be placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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