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Kinase inhibition can increase autophagy and reduce therapeutic efficacy, motivating combined use with autophagy inhibitors. The study evaluates FDA-approved sorafenib and hydroxychloroquine using computational modeling plus in vitro assays in KRAS-mutant MDA-MB-231 breast and A549 lung cancer cells.",{"@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/computational-experimental-repurposing-reveals-synergistic-sorafenibhydroxychloroquine-response-in-kras-mutant-breast-cancer/348997/",{"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/computational-experimental-repurposing-reveals-synergistic-sorafenibhydroxychloroquine-response-in-kras-mutant-breast-cancer/348997.png","ImageObject",300,407,{"name":92,"@type":93},"Alex Sinclair","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why combine kinase inhibition with autophagy inhibition for KRAS-mutant cancers?","Question",{"text":112,"@type":113},"KRAS-driven tumors rely on MAPK/ERK and PI3K/AKT signaling for growth and survival, and kinase inhibitors can upregulate autophagy, which may confer resistance. Adding an autophagy inhibitor is proposed to enhance antitumor benefit.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were sorafenib and hydroxychloroquine assessed for synergy in the study?",{"text":117,"@type":113},"The work combines molecular dynamics simulation metrics (RMSD, RMSF, Rg, hydrogen bonds, contact frequency, and MM/GBSA) with in vitro cytotoxicity and interaction analyses using MTT assays, Chou-Talalay Combination Index, and Dose Reduction Index.",{"name":119,"@type":110,"acceptedAnswer":120},"What outcome differences were observed between breast and lung cancer models?",{"text":121,"@type":113},"The sorafenib/HQ combination showed synergy in MDA-MB-231 breast cancer cells (with reported CI \u003C 1), while it showed antagonism in A549 lung cancer cells (CI > 1), indicating tumor-type dependence.","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},348997,1790173957,{"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":14,"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},1099523882182,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Abdelwahab etal. BMC Pharmacology and Toxicology (2026) 27:60  \n[https://doi.org/10.1186/s40360-026-01122-2](https://doi.org/10.1186/s40360-026-01122-2)  \nBMC Pharmacology and Toxicology  \nRESEARCH Open Access  \nComputational-experimental   \nrepurposing reveals synergistic sorafenib/ hydroxychloroquine response in KRAS-mutant breast cancer  \nMohammad M. Abdelwahab 1,2, Mahmoud Soliman3,4* and Amr Nassrallah2,5*  \nAbstract  \nBackground KRAS mutations are approximately 25% of human cancers, with particularly high incidence in breast and lung cancers, by constitutively triggering MAPK/ERK and PI3K/AKT pathways that advance proliferation, survival, and autophagy-mediated resistance. Targeting these pathways with kinase inhibitors upregulates autophagy, thereby diminishing therapeutic efficacy. Thus, combining kinase inhibitors with autophagy inhibitors offers a rational strategy to enhance antitumor benefits in KRAS-mutant malignancies. FDA-approved Sorafenib (multi-kinase inhibitor targeting Raf ) and Hydroxychloroquine (autophagy inhibitor) show promise for repurposing, as Sorafenib induces autophagy leading to resistance, warranting combination testing in KRAS-mutant models. This study integrates computational modeling and in vitro assays to evaluate their synergistic potential in MDA-MB-231 breast and A549 lung cancer cells.  \nMethods Raf-Sorafenib stability was evaluated using RMSD, RMSF, Rg, hydrogen bonds, contact frequency, and MM/GBSA for binding free energy in molecular dynamics simulations (100 ns, GROMACS with CHARMM36 force field) . MTT assays were used for cytotoxicity on MDA-MB-231, A549, and normal gingival fibroblasts (48 h treatment); Chou-Talalay Combination Index and Dose Reduction Index were used for synergy; Annexin V/PI flow cytometry was performed for apoptosis; PI staining was used for cell cycle; and ANOVA/Tukey’s test (GraphPad Prism, p \u003C 0. 05) was conducted for statistics.  \nResults Sorafenib bound Raf stably (RMSD ~ 0.25 nm protein/0 .15 nm ligand, G_bind − 49.90 ± 2.69 kcal/mol), with persistent interactions (3–4 H-bonds, key residues VAL471, LEU513) . IC50 values: Sorafenib 9.4 µM (MDA-MB-231), 12 µM (A549), 23.1 µM (fibroblasts); HQ 23. 6/62 .4/86 .2 µM; SN:2HQ ratio showed synergy in MDA-MB-231 (CI = 0 . 32, DRI 9.36 Sorafenib/4 .68 HQ at Fa = 0 . 5) but antagonism in A549 (CI > 1) . Combination enhanced late apoptosis/necrosis (49 .41%) in MDA-MB-231 with minimal normal cell cycle disruption.  \n*Correspondence:  \nMahmoud Soliman [mahmoud.e.soliman@pharma.asu.edu.eg](mahmoud.e.soliman@pharma.asu.edu.eg)[ ](mahmoud.e.soliman@pharma.asu.edu.eg)Amr Nassrallah [amr.nassrallah@ejust.edu.eg](amr.nassrallah@ejust.edu.eg)  \nFull list of author information is available at the end of the article  \n© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/.)[.](http://creativecommons.org/licenses/by/4.0/.)  \nAbdelwahab et al. BMC Pharmacology and Toxicology (2026) 27:60 Page 2 of 15  \nConclusions Sorafenib-HQ combination offers potent, context-specific synergy for KRAS-mutant breast cancer via Raf inhibition and autophagy blockade, enabling dose reductions and apopt","cbCaidUiMJjsxqJG","https://ap.wps.com/l/cbCaidUiMJjsxqJG","pdf",4284423,15,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusions\n# Introduction\n## KRAS signaling pathways and cancer biology\n## KRAS-autophagy relationship\n# Computational-experimental approach\n## Molecular dynamics and binding free energy\n## Cell-based synergy and apoptosis assays","[{\"question\":\"Why combine kinase inhibition with autophagy inhibition for KRAS-mutant cancers?\",\"answer\":\"KRAS-driven tumors rely on MAPK/ERK and PI3K/AKT signaling for growth and survival, and kinase inhibitors can upregulate autophagy, which may confer resistance. Adding an autophagy inhibitor is proposed to enhance antitumor benefit.\"},{\"question\":\"How were sorafenib and hydroxychloroquine assessed for synergy in the study?\",\"answer\":\"The work combines molecular dynamics simulation metrics (RMSD, RMSF, Rg, hydrogen bonds, contact frequency, and MM/GBSA) with in vitro cytotoxicity and interaction analyses using MTT assays, Chou-Talalay Combination Index, and Dose Reduction Index.\"},{\"question\":\"What outcome differences were observed between breast and lung cancer models?\",\"answer\":\"The sorafenib/HQ combination showed synergy in MDA-MB-231 breast cancer cells (with reported CI \\u003c 1), while it showed antagonism in A549 lung cancer cells (CI \\u003e 1), indicating tumor-type dependence.\"}]","Computational-experimental repurposing reveals synergistic sorafenib/hydroxychloroquine response in KRAS-mutant breast cancer | PDF",1790081088,38]