Oncogenic activation of PIK3CA in cancers:Emerging targeted therapies in precision oncology  

作　　者：Yuxiang Wang Valery Rozen Yiqing Zhao Zhenghe Wang 

机构地区：[1]Department of Genetics and Genome Sciences,Case Western Reserve University,Cleveland,OH 44106,USA [2]Case Comprehensive Cancer Center,Case Western Reserve University,Cleveland,OH 44106,USA [3]College of Human Medicine,Michigan State University,Grand Rapids,MI 49503,USA

出　　处：《Genes & Diseases》2025年第2期143-153,共11页基因与疾病(英文)

基　　金：supported by the National Institutes of Health (USA)grantsSR01CA196643,R01CA264320,R01CA260629,P50CA150964,and P30CA043703 to Zhenghe Wang.

摘　　要：Phosphoinositide 3-kinases(PI3Ks)are heterodimers consisting of a p110 catalytic subunit and a p85 regulatory subunit.The PlIK3CA gene,which encodes the p110a,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 p110a 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 p110a gained direct interaction with insulin receptor substrate 1(IRs-1)to activate the downstream signaling path-ways.Moreover,p85βproteins disassociate from helical domain mutant p110a,translocate into the nucleus,and stabilize enhancer of zeste homolog 1/2(EzH1/2).Due to the funda-mental role of Pl3Ka in tumor initiation and development,Pl3Ka-specific inhibitors,repre-sented 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 p110a mutant-specific inhibitors to circumvent on-target side effects becomes a new direction for targeting PIK3CA mutant can-cers.In this review,we briefly introduce the function of the Pl3K 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.

关 键 词：Hotspot mutation Isoform/mutant-specific inhibitors Metabolism PIK3CA Tumor microenvironment 

分 类 号：R73[医药卫生—肿瘤]