{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:46:14Z","timestamp":1787240774745,"version":"build-2736575974"},"reference-count":26,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"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":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Ewing sarcoma (ES) is an aggressive bone malignancy with poor outcomes for chemotherapy\u2010resistant patients, yet the mechanisms underlying vincristine resistance remain unclear. Here, we identify protein kinase inhibitor alpha (PKIA) as a critical driver of chemoresistance through cAMP\u2013EPAC signaling reprogramming. Transcriptomic analysis of vincristine\u2010resistant ES cells revealed PKIA upregulation, which correlated with poor survival in clinical cohorts (HR\u2009=\u20092.14,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001). Mechanistically, PKIA overexpression elevated intracellular cAMP levels but suppressed PKA activity, instead activating the noncanonical EPAC\u2013Rap1\u2013ERK pathway to promote drug efflux and survival. Pharmacological inhibition of EPAC with ESI\u201009 reversed resistance (IC~50~ reduction: 52%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01), while PKIA knockdown restored vincristine sensitivity in xenografts. Strikingly, PKIA exhibited a dual role, with low expression in primary ES (potentially tumor\u2010suppressive) and high expression in resistant\/metastatic tumors (prosurvival), mirroring observations in prostate and hepatocellular cancers. Our work establishes PKIA as a therapeutic vulnerability and supports targeting the cAMP\u2013EPAC axis to overcome chemoresistance in high\u2010risk ES.\n                  <\/jats:p>","DOI":"10.1002\/mc.70065","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T19:23:57Z","timestamp":1764357837000},"page":"202-215","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Protein Kinase Inhibitor Alpha Drives Vincristine Resistance in Ewing Sarcoma via cAMP\u2013EPAC Signaling Reprogramming"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6823-3968","authenticated-orcid":false,"given":"Xin","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery The Second Affiliated Hospital of Chongqing Medical University Chongqing China"},{"name":"Department of Orthopedic Surgery Chongqing University Jiangjin Hospital, Centre Hospital of Jiangjin District Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yating","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Chongqing University Jiangjin Hospital, Centre Hospital of Jiangjin District Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery The Second Affiliated Hospital of Chongqing Medical University Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4933-541X","authenticated-orcid":false,"given":"Zhongliang","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery The Second Affiliated Hospital of Chongqing Medical University Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.28355"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-8049(11)70206-4"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.34942"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.00053"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCO.0000000000001048"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2024.01.007"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1089\/jayao.2023.0185"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.2174\/1574888X17666220627114710"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15030769"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-024-01524-x"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2023.153582"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-024-01900-y"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21186489"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202001515R"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.npep.2005.10.002"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-020-0522-3"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.1025900"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-023-02807-1"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-022-00838-z"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202007207"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.110014"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11132020"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-22-0479"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2020.101093"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2024.167114"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01717-2"}],"container-title":["Molecular 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