{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:07:18Z","timestamp":1774570038829,"version":"3.50.1"},"reference-count":73,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"814","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,9,3]]},"abstract":"<jats:p>\n            <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n            is among the most frequently mutated oncogenes in cancer, and for decades, efforts at pharmacological blockade of its function in solid cancers have been unsuccessful. A notable advance in this endeavor is the recent development of small-molecule KRAS inhibitors, which enable direct targeting of the mutant oncoprotein. Here, we comprehensively evaluated the preclinical efficacy of BI-2493, a first-in-class allele-agnostic mutant-KRAS inhibitor (panKRASi), in pancreatic ductal adenocarcinoma (PDAC). We report effective tumor growth suppression across a broad range of models, including cell lines, patient-derived xenografts (PDXs), and syngeneic orthotopic models, and prolonged survival in genetically engineered mouse models. Overall, transcriptomic, proteomic, and phosphoproteomic profiling of panKRASi-treated models confirmed RAS pathway inhibition along with up-regulation of LKB1\/AMPK (liver kinase B1\/AMP-activated protein kinase) targets. In panKRASi-treated immune-replete models, we observed increased intratumoral CD8\n            <jats:sup>+<\/jats:sup>\n            effector T cells and decreased infiltration of myeloid cells, along with remodeling of the tumor microenvironment (TME), enabling responses to immune checkpoint blockade. In the long term, emergence of resistance to panKRASi monotherapy was associated with increased YAP signaling within tumor cells and enhanced expression of immune checkpoints in the TME that impede effective T cell function. Our multifaceted approach identified potential combinatorial approaches for generating sustained responses to panKRASi.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adt5511","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T17:58:18Z","timestamp":1756922298000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":4,"title":["An allele-agnostic mutant-KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4092-4991","authenticated-orcid":true,"given":"Kathleen M.","family":"McAndrews","sequence":"first","affiliation":[{"name":"University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}]},{"given":"Francesca","family":"Paradiso","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0570-4416","authenticated-orcid":true,"given":"Clint A.","family":"Stalnecker","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."},{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8013-1294","authenticated-orcid":true,"given":"Benson S.","family":"Chellakkan","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1822-4526","authenticated-orcid":true,"given":"Fredrik I.","family":"Thege","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0511-1888","authenticated-orcid":true,"given":"David H.","family":"Peng","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}]},{"given":"Barbara A.","family":"Moreno Diaz","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}]},{"given":"Hikaru","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}]},{"given":"Sarah I.","family":"Patel","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6503-6851","authenticated-orcid":true,"given":"Krishnan K.","family":"Mahadevan","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}]},{"given":"Michelle L.","family":"Kirtley","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson 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M. McAndrews K. K. Mahadevan B. Li A. M. Sockwell S. J. Morse P. J. Kelly S. I. Patel M. L. Kirtley B. A. Moreno Diaz H. Lyu X. Zhou H. Sugimoto L. K. Sthanam M. R. Conner S. V. Kumbhar K. A. Arian Y. Barekatain F. Paradiso P. A. Guerrero V. Bernard N. Sobhani A. N. Camacho-Acevedo K. E. Bornes P. T. Tran A. Maitra T. P. Heffernan R. Kalluri CDK8 remodels the tumor microenvironment to resist the therapeutic efficacy of targeted KRASG12D inhibition in pancreatic ductal adenocarcinoma. bioRxiv 2025.01.29.635543 [Preprint] (2025). https:\/\/doi.org\/10.1101\/2025.01.29.635543.","DOI":"10.1101\/2025.01.29.635543"},{"key":"e_1_3_2_58_2","doi-asserted-by":"crossref","unstructured":"V. S. LeBleu B. G. Smaglo K. K. Mahadevan M. L. Kirtley K. M. McAndrews M. Mendt S. Yang A. S. Maldonado H. Sugimoto M. E. Salvatierra L. M. Solis Soto R. Finch M. Gagea A. C. Fluty S. J. Ludtke J. J. Lee A. K. Jain G. Varadhachary R. T. Shroff A. Maitra E. Shpall R. Kalluri S. Pant KRASG12D-specific targeting with engineered exosomes reprograms the immune microenvironment to enable efficacy of immune checkpoint therapy in PDAC patients. medRxiv 2025.03.03.25322827 [Preprint] (2025). https:\/\/doi.org\/10.1101\/2025.03.03.25322827.","DOI":"10.1101\/2025.03.03.25322827"},{"key":"e_1_3_2_59_2","doi-asserted-by":"crossref","unstructured":"K. K. Mahadevan A. S. Maldonado B. Li A. A. Bickert A. Perdyan S. V. Kumbhar S. Piya A. Sockwell S. J. Morse K. Arian H. Sugimoto S. Shalapour D. S. Hong T. P. Heffernan A. Maitra R. Kalluri Inhibitors of oncogenic Kras specifically prime CTLA4 blockade to transcriptionally reprogram Tregs and overcome resistance to suppress pancreas cancer. bioRxiv 2025.02.28.640711 [Preprint] (2025). https:\/\/doi.org\/10.1101\/2025.02.28.640711.","DOI":"10.1101\/2025.02.28.640711"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-1475"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03918"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-213X-1-4"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27349-7"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature22341"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-0442"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-4009"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2021109470"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M113.036392"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1111\/andr.13314"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1214\/16-AOAS920"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btac665"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4887"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-32-9755-5_7"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adt5511","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T17:58:24Z","timestamp":1756922304000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adt5511"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,3]]},"references-count":73,"journal-issue":{"issue":"814","published-print":{"date-parts":[[2025,9,3]]}},"alternative-id":["10.1126\/scitranslmed.adt5511"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adt5511","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,3]]},"assertion":[{"value":"2024-10-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadt5511"}}