[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-381907-105":59,"doc-detail-381907-en":131},{"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":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","hoxc6-drives-a-therapeutically-targetable-pancreatic-cancer-growth-and-metastasis-pathway-summary","HOXC6 drives a therapeutically targetable pancreatic cancer growth and metastasis pathway - Summary","","Pancreatic ductal adenocarcinoma (PDAC) lacks effective therapies, prompting investigation of transcriptional regulators. HOXC6 is overexpressed in most PDACs, and HOXC6 inhibition blocks tumor growth and metastasis by transcriptionally activating MSK1 while suppressing PPP2R2B. PPP2R2B loss activates the mTOR pathway to facilitate PDAC growth, and MSK1 supports survival through DDX17-mediated apoptosis suppression. Combined MSK1/mTOR inhibition suppresses PDAC in mouse models, while resistance maps to IGF1R dependence that is targetable with an IGF1R inhibitor, and trametinib enhances efficacy.",{"@graph":69,"@context":123},[70,84,106],{"@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/hoxc6-drives-a-therapeutically-targetable-pancreatic-cancer-growth-and-metastasis-pathway-summary/381907/",{"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/hoxc6-drives-a-therapeutically-targetable-pancreatic-cancer-growth-and-metastasis-pathway-summary/381907.png","ImageObject",300,407,{"name":92,"@type":93},"Blitz","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What role does HOXC6 play in pancreatic cancer?","Question",{"text":113,"@type":114},"HOXC6 overexpression facilitates PDAC tumor growth and metastasis. Inhibiting HOXC6 blocks these processes.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does HOXC6 regulate PDAC-promoting and PDAC-inhibitory proteins?",{"text":118,"@type":114},"HOXC6 transcriptionally activates MSK1 and suppresses PPP2R2B. PPP2R2B suppression activates the mTOR pathway and supports PDAC growth.",{"name":120,"@type":111,"acceptedAnswer":121},"How does drug resistance to MSK1/mTOR inhibition arise and how is it overcome?",{"text":122,"@type":114},"MSK1/mTOR inhibitor-resistant PDACs show activated IGF1R signaling. These resistant cells are eradicated by an IGF1R inhibitor, and trametinib can enhance dual inhibition efficacy.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},381907,1790701095,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},24464137899374,"https://us-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","Article  \nHOXC6 drives a therapeutically targetable pancreatic cancer growth and metastasis pathway by regulating MSK1 and PPP2R2B  \nAuthors  \nParmanand Malvi, Suresh Chava, Guoping Cai, ..., Michael R. Green, Romi Gupta, Narendra Wajapeyee  \nCorrespondence  \n[romigup@uab.edu](romigup@uab.edu) (R.G.),  \n[nwajapey@uab.edu](nwajapey@uab.edu) (N.W.)  \nIn brief  \nMalvi et al. identify HOXC6 as a facilitatorof PDAC tumor growth and metastasis. This function is, in part, achieved by regulating the expression of HOXC6 target genes, MSK1, and PPP2R2B. Furthermore, dual pharmacological inhibition of MSK1 and mTOR or combinatorially with MEK inhibitor trametinib suppresses PDAC.  \nd HOXC6 overexpression promotes PDAC tumor growth and metastasis  \nd HOXC6 activates MSK1 kinase and suppresses PPP2R2B protein to promote PDAC  \nd Combinatorial pharmacological suppression of MSK1 and mTOR pathway inhibits PDAC  \nd MSK1/mTOR inhibitor-resistant PDACs acquire dependency on IGF1R signaling pathway  \nMalvi et al., 2023, Cell Reports Medicine 4, 101285 November 21, 2023 ª 2023 The Authors.  \n[https://doi.org/10.1016/j.xcrm.2023.101285](https://doi.org/10.1016/j.xcrm.2023.101285)  \nll  \nll  \nOPEN ACCESS  \nArticle  \nHOXC6 drives a therapeutically targetable pancreatic cancer growth and metastasis pathway by regulating MSK1 and PPP2R2B  \nParmanand Malvi,1 Suresh Chava,1 Guoping Cai,2 Kai Hu,3 Lihua Julie Zhu,3,4,5 Yvonne J.K. Edwards,1 Michael R. Green,3 Romi Gupta,1,6,* and Narendra Wajapeyee1,6,7,*  \n1Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA  \n2Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA  \n3Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA  \n4Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA  \n5Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA  \n6O’Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA  \n7Lead contact  \n*Correspondence: [romigup@uab.edu](romigup@uab.edu) (R.G.), [nwajapey@uab.edu](nwajapey@uab.edu) (N.W.) [https://doi.org/10.1016/j.xcrm.2023.101285](https://doi.org/10.1016/j.xcrm.2023.101285)  \nSUMMARY  \nPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective therapies. Here, we demonstrate that the transcription factor, homeobox C6 (HOXC6), is overexpressed in most PDACs, and its inhibition blocks PDAC tumor growth and metastasis. HOXC6 transcriptionally activates tumor-promoting kinase MSK1 and suppresses tumor-inhibitory protein PPP2R2B in PDAC. HOXC6-induced PPP2R2B suppression causes mammalian target of rapamycin (mTOR) pathway activation, which facilitates PDAC growth. Also, MSK1 upregulation by HOXC6 is necessary for PDAC growth because of its ability to suppress apoptosis via its substrate DDX17 . Combinatorial pharmacological inhibition of MSK1 and mTOR potently suppressed PDAC tumor growth and metastasis in PDAC mouse models. PDAC cells with acquired resistance to MSK1/mTOR-inhibitors displayed activated insulin-like growth factor 1 receptor (IGF1R) signaling and were successfully eradicated by IGF1R inhibitor. Furthermore, MEK inhibitor trametinib enhanced the efficacy of dual MSK1 and mTOR inhibition. Collectively, these results identify therapeutic vulnerabilities of PDAC and an approach to overcome acquired drug resistance to prolong therapeutic benefit.  \nINTRODUCTION  \nPancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and accounts for more than 400,000 deaths worldwide annually.1 The 5-year overall survival rate for patients with advanced/unresectable PDAC is estimated to be approximately 12% for all Surveillance, Epidemiology, and End Results stages combined and decreases to approximately 3% for pati","cbCaiqa74gxHjNWN","https://ap.wps.com/l/cbCaiqa74gxHjNWN","pdf",10229095,31,"English","# Summary\n# Introduction\n## HOXC6 and PDAC dependency\n## Therapeutic targeting strategy","[{\"question\":\"What role does HOXC6 play in pancreatic cancer?\",\"answer\":\"HOXC6 overexpression facilitates PDAC tumor growth and metastasis. Inhibiting HOXC6 blocks these processes.\"},{\"question\":\"How does HOXC6 regulate PDAC-promoting and PDAC-inhibitory proteins?\",\"answer\":\"HOXC6 transcriptionally activates MSK1 and suppresses PPP2R2B. PPP2R2B suppression activates the mTOR pathway and supports PDAC growth.\"},{\"question\":\"How does drug resistance to MSK1/mTOR inhibition arise and how is it overcome?\",\"answer\":\"MSK1/mTOR inhibitor-resistant PDACs show activated IGF1R signaling. These resistant cells are eradicated by an IGF1R inhibitor, and trametinib can enhance dual inhibition efficacy.\"}]","HOXC6 drives a therapeutically targetable pancreatic cancer growth and metastasis pathway - Summary | PDF",1790247704,78]