{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:34:20Z","timestamp":1792787660417,"version":"4.5.0"},"reference-count":60,"publisher":"American Society for Clinical Investigation","issue":"10","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":57,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute","award":["CA169702,CA197296,CA247886,CA062924,CA006973,CA126607,P30CA054174"],"award-info":[{"award-number":["CA169702,CA197296,CA247886,CA062924,CA006973,CA126607,P30CA054174"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,15]]},"abstract":"<jats:p>\n                    Single-agent anti-PD-1 antibodies are ineffective for pancreatic ductal adenocarcinoma (PDAC) due to the immunosuppressive tumor-microenvironment (TME).\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutations contribute to the inflammatory TME and therapeutic resistance by upregulating IL-8 via MAPK pathways. Thus, this study attempted to overcome the resistance to anti-PD-1 antibodies by targeting downstream KRAS-effectors. The study found that the resistance to anti-PD-1 antibodies can be overcome through MEK1\/2-inhibition. The combination of anti-PD-1 antibodies and MEK inhibitors displayed antitumor activity in Kras mutated (Kras\n                    <jats:sup>mut<\/jats:sup>\n                    ) KPC mouse tumors, but not WT (Kras\n                    <jats:sup>WT<\/jats:sup>\n                    ) Panc02 tumors. The combination of anti-PD-1 antibodies and MEK inhibitors induced recruitment of tumor-associated neutrophils (TANs) via CXCR2, an IL-8 receptor, and increased memory CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells and IFN-\u03b3 production in treatment-sensitive tumors. However, larger tumors still resisted the combination of anti-PD-1 antibody and MEK inhibitor, likely due to hypoxia\/necrosis-induced NETosis and associated paucity of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. The subsequent addition of anti-CXCR2 antibody overcame this resistance by blocking TAN-infiltration to hypoxic\/necrotic areas. Consistently, a risk-score based on the NETosis-MAPK signaling interaction is significantly associated with poorer survival in human PDAC. This study thus provides a new venue for overcoming resistance to strategies targeting KRAS signaling.\n                  <\/jats:p>","DOI":"10.1172\/jci196622","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T17:25:32Z","timestamp":1773941132000},"source":"Crossref","is-referenced-by-count":5,"title":["CXCR2 blockade overcomes the NETosis-mediated resistance to MEK inhibition in pancreatic cancer models"],"prefix":"10.1172","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9278-8541","authenticated-orcid":true,"given":"Brian","family":"Herbst","sequence":"first","affiliation":[{"name":"Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center,"},{"name":"Graduate Program in Cellular and Molecular Medicine,"},{"name":"Pancreatic Cancer Precision Medicine Center of Excellence Program,"},{"name":"Bloomberg-Kimmel Institute for Cancer Immunotherapy,"},{"name":"Skip Viragh Center for Pancreatic Cancer, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Blair","sequence":"additional","affiliation":[{"name":"Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center,"},{"name":"Pancreatic Cancer Precision Medicine Center of Excellence Program,"},{"name":"Skip Viragh Center for Pancreatic Cancer, and"},{"name":"Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center,"},{"name":"Pancreatic Cancer Precision Medicine Center of Excellence Program,"},{"name":"Bloomberg-Kimmel Institute for Cancer Immunotherapy,"},{"name":"Mays Cancer Center, University of Texas Health San Antonio MD Anderson, San Antonio, Texas, 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