{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T19:44:53Z","timestamp":1787859893639,"version":"build-2784847793"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":7,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Egypt Japan University"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Pharmacol Toxicol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\u00a0h 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\u2019s test (GraphPad Prism,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) was conducted for statistics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Sorafenib bound Raf stably (RMSD\u2009~\u20090.25\u00a0nm protein\/0.15\u00a0nm ligand, G_bind\u2009\u2212\u200949.90\u2009\u00b1\u20092.69\u00a0kcal\/mol), with persistent interactions (3\u20134\u00a0H-bonds, key residues VAL471, LEU513). IC50 values: Sorafenib 9.4 \u00b5M (MDA-MB-231), 12 \u00b5M (A549), 23.1 \u00b5M (fibroblasts); HQ 23.6\/62.4\/86.2 \u00b5M; SN:2HQ ratio showed synergy in MDA-MB-231 (CI\u2009=\u20090.32, DRI 9.36 Sorafenib\/4.68 HQ at Fa\u2009=\u20090.5) but antagonism in A549 (CI\u2009&gt;\u20091). Combination enhanced late apoptosis\/necrosis (49.41%) in MDA-MB-231 with minimal normal cell cycle disruption.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Sorafenib-HQ combination offers potent, context-specific synergy for KRAS-mutant breast cancer via Raf inhibition and autophagy blockade, enabling dose reductions and apoptosis enhancement. Tumor-type dependence (synergy vs. antagonism) highlights need for patient stratification; findings support repurposing with limited normal cell impact.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40360-026-01122-2","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T12:05:13Z","timestamp":1775131513000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Computational-experimental repurposing reveals synergistic sorafenib\/hydroxychloroquine response in KRAS-mutant breast cancer"],"prefix":"10.1186","volume":"27","author":[{"given":"Mohammad M.","family":"Abdelwahab","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Soliman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amr","family":"Nassrallah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"issue":"5","key":"1122_CR1","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","volume":"144","author":"D Hanahan","year":"2011","unstructured":"Hanahan D, Weinberg RA. 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