[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-370084-105":59,"doc-detail-370084-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","from-pik3ca-mutations-to-rational-pi3k-inhibition-for-the-treatment-of-colorectal-cancer","From PIK3CA Mutations to Rational PI3K Inhibition for the Treatment of Colorectal Cancer","","Kinase PI3K inhibitors have advanced clinically, yet colorectal cancer has shown limited benefit despite frequent PIK3CA gene mutations. This shortfall is linked to molecular resistance mechanisms not adequately addressed during development, including concomitant mutations and copy-number alterations in receptor tyrosine kinase pathway genes such as KRAS and BRAF. Earlier trials often did not require PIK3CA mutation status, and even when included, they did not account for pathway gene variants and for differences in mutation sites within PIK3CA that may influence functional impact and drug effectiveness. The review summarizes PI3K inhibitor development progress, key development hurdles, and opportunities for improvement.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/from-pik3ca-mutations-to-rational-pi3k-inhibition-for-the-treatment-of-colorectal-cancer/370084/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/from-pik3ca-mutations-to-rational-pi3k-inhibition-for-the-treatment-of-colorectal-cancer/370084.png","ImageObject",300,407,{"name":92,"@type":93},"anakgang17","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":29},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why have PI3K inhibitors been less effective in colorectal cancer than in metastatic breast cancer?","Question",{"text":112,"@type":113},"Despite frequent PIK3CA mutations, PI3K inhibitors show limited success in colorectal cancer because resistance is driven by additional molecular alterations such as KRAS/BRAF changes and other pathway alterations that were not adequately considered during development.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What did early clinical trials of PI3K inhibitors often fail to include as selection criteria?",{"text":117,"@type":113},"Most early trials did not mandate molecular alterations of PIK3CA as an inclusion criterion, limiting the ability to identify which molecular contexts respond.",{"name":119,"@type":110,"acceptedAnswer":120},"How can mutation context within the PIK3CA gene affect inhibitor effectiveness?",{"text":121,"@type":113},"The review notes that the specific type and location of PIK3CA mutations (e.g., catalytic domain vs helical domain) may change functional consequences and thereby influence how well inhibitors work.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},370084,1790843284,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":29,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},962090883568,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","Molecular Diagnosis & Therapy (2026) 30:5–17 [https://doi.org/10.1007/s40291-025-00815-4](https://doi.org/10.1007/s40291-025-00815-4)  \nFrom PIK3CA Mutations to Rational PI3K Inhibition for the Treatment of Colorectal Cancer  \nIoannis A. Voutsadakis1,2,3  \nReceived: 8 July 2025 / Accepted: 10 September 2025 / Published online: 18 September 2025 © The Author(s) 2025  \nAbstract  \nInhibitors of kinase PI3K have been in clinical development for several years but only two drugs, the alpha catalytic sub-unit specific inhibitor alpelisib and more recently inavolisib, also an inhibitor of the alpha catalytic sub-unit, have been approved fora cancer indication, in metastatic breast cancer. In colorectal cancer, despite a high prevalence of PIK3CA gene mutations, PI3K inhibitors have met with limited success, and development has mostly been halted or stagnated. Inherent resistance of colorectal cancer cells to PI3K inhibitors relate to the molecular alterations ofthis cancer, which include concomitant mutations and copy number alterations in other key players of the receptor tyrosine kinase pathways, including KRAS and BRAF. These have not been addressed adequately during clinical development of PI3K inhibitors. Most early trials examining PI3K inhibitors did not mandate for molecular alterations of PIK3CA as an inclusion criterion. These trials have sought to potentiate the action of other inhibitors of receptor tyrosine kinase pathways using PI3K inhibitors as a non-specific prevention against feedback resistance development. In addition, trials that included patients with PIK3CA-mutated cancers failed to consider mutations in other genes of the pathway, which may be related to primary or induced resistance. Other factors, such as the specific type of PIK3CA mutations arising in the catalytic domain, the helical domain, or other areas of the gene, which may affect the mutation functional repercussions and the inhibitor effectiveness, have not been fully taken into consideration. This review details the progress of PI3Kinhibitors’ development in colorectal cancer, addresses hurdles in development, and proposes areas for potential advancement.  \nKey Points  \nPI3K is a lipid kinase strategically placed as a node in receptor tyrosine kinase transduction pathways that are important in carcinogenesis. In colorectal cancer the gene encoding for the alpha catalytic sub-unit of PI3K, PIK3CA, is mutated in about one in five cases.  \nDespite success in breast cancer, efforts to target PI3K with specific inhibitors in colorectal cancer have not been fruitful.  \n* Ioannis A. Voutsadakis  \n[ivoutsadakis@yahoo.com](ivoutsadakis@yahoo.com); [ivoutsadakis@nosm.ca](ivoutsadakis@nosm.ca)  \n1 Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City,  \nIA 52240, USA  \n1 Introduction  \nPI3K is a key kinase in the PI3K/AKT/mTOR pathway signaling downstream of receptor tyrosine kinases and often deregulated in cancer [1] . In colorectal cancer, the pathway together with the parallel running and intertwined KRAS/BRAF/MEK pathway is deregulated in the majority of cases due to genomic alterations, most frequently oncogenic mutations in KRAS [2] . PIK3CA, the gene encoding for the α catalytic sub-unit of PI3K, p110α, is mutated in about a fifth to a fourth of colorectal cancer cases [3 , 4] . The α catalytic sub-unit is one of the four alternative catalytic units of PI3K, the three others being p110β, p110γ, and p110δ, which combine with one of five alternative regulatory sub-units to form the holoenzyme (Fig. 1) [5] . PI3K is activated by receptor tyrosine kinases directly and  \n2 University of Iowa Carver College of Medicine, Iowa City, IA, USA  \n3 Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, ON, Canada  \nthrough KRAS, and transduces signals of cell growth, proliferation, and survival through kinase AKT and other effectors (Fig. 2) . Although co-occurr","cbCainbITHYnErrV","https://ap.wps.com/l/cbCainbITHYnErrV","pdf",693936,13,"English","# Abstract\n# Key Points\n## PI3K role and PIK3CA mutation prevalence in colorectal cancer\n## Pathway interactions (KRAS/BRAF/MEK and PI3K/AKT/mTOR)\n## Mutation co-occurrence patterns and implications\n## Molecular diagnosis approaches (tumor vs circulating free DNA)\n# Development hurdles and future directions","[{\"question\":\"Why have PI3K inhibitors been less effective in colorectal cancer than in metastatic breast cancer?\",\"answer\":\"Despite frequent PIK3CA mutations, PI3K inhibitors show limited success in colorectal cancer because resistance is driven by additional molecular alterations such as KRAS/BRAF changes and other pathway alterations that were not adequately considered during development.\"},{\"question\":\"What did early clinical trials of PI3K inhibitors often fail to include as selection criteria?\",\"answer\":\"Most early trials did not mandate molecular alterations of PIK3CA as an inclusion criterion, limiting the ability to identify which molecular contexts respond.\"},{\"question\":\"How can mutation context within the PIK3CA gene affect inhibitor effectiveness?\",\"answer\":\"The review notes that the specific type and location of PIK3CA mutations (e.g., catalytic domain vs helical domain) may change functional consequences and thereby influence how well inhibitors work.\"}]","From PIK3CA Mutations to Rational PI3K Inhibition for the Treatment of Colorectal Cancer | PDF",1790186625,33]