{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T04:08:45Z","timestamp":1779422925276,"version":"3.53.1"},"reference-count":22,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Fundamemntal Clinical Pharma"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Resistance to B\u2010Raf inhibitors in melanoma poses a significant challenge to effective treatment. This study investigates the synergistic effects of capivasertib, an Akt pathway inhibitor, in combination with B\u2010Raf inhibitors (vemurafenib and encorafenib) in B\u2010Raf\u2010mutated melanoma models. Combination index analysis demonstrated strong synergy between capivasertib and B\u2010Raf inhibitors in melanoma cells. In contrast, combinations of capivasertib with standard chemotherapeutics were antagonistic, underscoring the specificity of the interaction. Mechanistic studies revealed that capivasertib effectively suppressed Akt signaling. Synergism was abolished in Akt\u2010overexpressing cells, confirming Akt's role in the observed combination effects. The combination treatments significantly reduced tumor growth, with tumor volumes in the capivasertib\u2010vemurafenib and capivasertib\u2010encorafenib groups reduced by ~70% relative to control. Notably, this inhibition was sustained for at least 8\u2009weeks, with tumors in the combination groups remaining minimal, while those in the control group reached maximal size by Week 4. Systemic toxicity analyses revealed no significant changes in body weight or serum markers of pancreatic, kidney, or liver function. These findings establish capivasertib and B\u2010Raf inhibitor combinations as a safe and effective strategy for overcoming resistance B\u2010Raf\u2010mutated melanoma, providing new insights into the potential of dual pathway targeting.<\/jats:p>","DOI":"10.1111\/fcp.70088","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:04:53Z","timestamp":1776816293000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual Targeting of Akt and MAPK Pathways With Capivasertib and B\u2010Raf Inhibitors Synergistically Suppresses Tumor Growth in B\u2010Raf\u2010Mutated Melanoma Models"],"prefix":"10.1111","volume":"40","author":[{"given":"Jun","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Oncology Xiangyang No.1 People's Hospital, Hubei University of Medicine  Xiangyang Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3500-1850","authenticated-orcid":false,"given":"Lingling","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Oncology Xiangyang No.1 People's Hospital, Hubei University of Medicine  Xiangyang Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Oncology Xiangyang No.1 People's Hospital, Hubei University of Medicine  Xiangyang Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4424-0083","authenticated-orcid":false,"given":"Baoxue","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Dermatology Xiangyang No.1 People's Hospital, Hubei University of Medicine  Xiangyang Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-023-14702-x"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/ced.12015"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15164026"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1103782"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15153754"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12918-018-0554-1"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11864-022-01006-7"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm301762v"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S300195"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-019-0827-1"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1418163112"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2010.11.023"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0028973"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389450114666140106100909"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.breast.2022.03.018"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/fcp.13042"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e33567"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1105358"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c00075"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.117.110759"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2021.05.005"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.04034"}],"container-title":["Fundamental &amp; 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