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Polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed to disrupt hyperactive mutant KRAS in cancer. PCAI effects on KRAS downstream signaling and viability were assessed in PANC-1 and MIAPaCa-2 cells. NSL-YHJ-2-27 increased phosphorylation of MAPK components and elevated pAKT while depleting monomeric G-proteins, enhanced reactive oxygen species, altered gene expression, inhibited migration, and induced apoptosis in 3D spheroids, suggesting potential targeted pan-KRAS therapy.",{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/the-anticancer-effects-of-pcais-in-pancreatic-cancer-cells-involve-mapk-and-pi3kakt-pathways-hyperactivation/353040/",{"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/the-anticancer-effects-of-pcais-in-pancreatic-cancer-cells-involve-mapk-and-pi3kakt-pathways-hyperactivation/353040.png","ImageObject",300,407,{"name":92,"@type":93},"supergirl","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-27","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":19},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What unmet medical need does the study address?","Question",{"text":112,"@type":113},"The study targets the unmet need for effective drugs against KRAS-driven cancers, especially those with mutant KRAS signaling.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do PCAIs affect MAPK and PI3K/AKT signaling in pancreatic cancer cells?",{"text":117,"@type":113},"In PANC-1 cells treated with NSL-YHJ-2-27, MAPK pathway phosphorylation (BRAF, MEK1/2, ERK1/2, p90RSK) increases, and pAKT (Ser473 and Thr308) phosphorylation is elevated, indicating pathway hyperactivation downstream effects.",{"name":119,"@type":110,"acceptedAnswer":120},"What functional anti-tumor outcomes do PCAIs show in the reported assays?",{"text":121,"@type":113},"PCAIs reduce monomeric G-proteins, increase reactive oxygen species, significantly change gene expression after RNA sequencing, inhibit pancreatic cancer cell migration, and induce apoptosis in PANC-1 and MIAPaCa-2 3D spheroids.","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},353040,1790169741,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":19,"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},962088121634,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","[www.oncotarget.com](www.oncotarget.com) Oncotarget, 2026, Vol. 17, pp: 268-290  \nResearch Paper  \nThe anticancer effects of PCAIs in pancreatic cancer cells involve MAPK and PI3K/AKT pathways hyperactivation  \nKweku Ofosu-Asante 1, Jassy Mary S . Lazarte 1, Amarender Goud Burra 1 and  \nNazarius S . Lamango 1  \n1 Florida A&M University College of Pharmacy Pharmaceutical Sciences, Institute of Public Health, Tallahassee, FL 32307, USA Correspondence to: Nazarius S. Lamango, [email](email: nazarius.lamango@famu.edu)[: nazarius.lamango@famu.edu](email: nazarius.lamango@famu.edu)  \nKeywords: PCAIs; PDAC; MAPK; PI3K/AKT; KRAS  \nReceived: October 09, 2025 Accepted: April 30, 2026 Published: June 03, 2026  \nCopyright: © 2026 Ofosu-Asante et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4 .0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.  \nABSTRACT  \nThere remains an unmet need for effective drugs targeting KRAS-driven cancers.  \nPolyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed to disrupt hyperactive mutant KRAS in cancer. Here, we determined the effects of PCAIs on the viability and downstream mediators of KRAS on pancreatic cancer-derived PANC-1 and MIAPaCa-2 cells. NSL-YHJ-2-45 and NSL-YHJ-2-27 were the most potent of the analogs with EC50 values of 3.6 and 3.8 µM, respectively. NSL-YHJ-2-27 treatment of PANC-1 cells stimulated BRAF, MEK 1/2, ERK 1/2 and p90RSK phosphorylation levels by 64 to 150% while CRAF phosphorylation significantly decreased by 27% .  \nFurthermore, 5 µM NSL-YHJ-2-27 depleted 20 to 61% of the monomeric G-proteins, CDC42, RHOA and RAC 1/2/3 while increasing pAKT (Ser 473) and pAKT (Thr 308) phosphorylation by 72 and 190%, respectively. Reactive oxygen species production significantly increased at 3 µM NSL-YHJ-27 in PANC-1 and MIA PaCa-2 by 2-and 9-fold, respectively. Bulk RNA sequencing analysis revealed that treatment of MIA PaCa-2 cells with 3 µM NSL-YHJ-27 resulted in significant differential expression of 88 genes. NSLYHJ-2-27 at 1 µM inhibited over 90% of pancreatic cancer cell migration.  \nThe PCAIs induced apoptosis in both PANC-1 and MIA PaCa-2 3D spheroids while doubling caspase 3/7 activity in PANC-1 cells. Taken together, these data obtained using pancreatic cancer cells with KRAS mutations suggest the ability of the PCAIs to prevent metastasis and tumor growth, strongly indicating their potential to serve as effective targeted therapies for treating cancer types driven by the multiple mutant forms of KRAS.  \nINTRODUCTION  \nThe RAS family of genes, including KRAS, NRAS, and HRAS, plays a pivotal role in cellular signaling pathways that regulate cell growth, differentiation, and survival [1]. Among them, KRAS is the most mutated in various cancers. These proteins act as molecular switches, cycling between GTP-bound active and GDP-bound inactive states as they play critical signal transduction roles from cell surface receptors to intracellular effectors [2] . KRAS mutations are diverse, with specific variants associated with different types of cancer and clinical outcomes [3] . The most common mutations are on codons  \n12, 13, and 61 that constitute hotspots for point mutations. Among these, G12C, G12D, G12V, and G13D are the most frequently observed. The mutations impair GTP hydrolysis, leading to constitutive activation of KRAS signaling that result in uncontrolled cell proliferation and tumorigenesis [4, 5] .  \nThe mutations drive approximately 30% of all human cancers, making them one of the most significant targets in oncological research [6, 7] . Specifically, KRAS mutations are observed in nearly 25% of all cancers diagnosed in the U.S, with prevalence as high as 90% of pancreatic adenocarcinomas, 40% of colorectal cancers, and 36% of non-small cell lung cancers (NSCLC) [3, 7, 8] .  \nThese mutations drive the aggressive natur","cbCaio3PNbeM40m5","https://ap.wps.com/l/cbCaio3PNbeM40m5","pdf",8638614,23,"English","# Abstract\n## Introduction","[{\"question\":\"What unmet medical need does the study address?\",\"answer\":\"The study targets the unmet need for effective drugs against KRAS-driven cancers, especially those with mutant KRAS signaling.\"},{\"question\":\"How do PCAIs affect MAPK and PI3K/AKT signaling in pancreatic cancer cells?\",\"answer\":\"In PANC-1 cells treated with NSL-YHJ-2-27, MAPK pathway phosphorylation (BRAF, MEK1/2, ERK1/2, p90RSK) increases, and pAKT (Ser473 and Thr308) phosphorylation is elevated, indicating pathway hyperactivation downstream effects.\"},{\"question\":\"What functional anti-tumor outcomes do PCAIs show in the reported assays?\",\"answer\":\"PCAIs reduce monomeric G-proteins, increase reactive oxygen species, significantly change gene expression after RNA sequencing, inhibit pancreatic cancer cell migration, and induce apoptosis in PANC-1 and MIAPaCa-2 3D spheroids.\"}]","The anticancer effects of PCAIs in pancreatic cancer cells involve MAPK and PI3K/AKT pathways hyperactivation | PDF",1790102700,58]