{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T18:38:11Z","timestamp":1775500691026,"version":"3.50.1"},"posted":{"date-parts":[[2026,4,3]]},"group-title":"Cancer Biology","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["Grant Nos. 82372884, 82573758, 2022hwyq29 to H.S., 82372644 to F.Y., 82120108012 and 81930086 to B.S."],"award-info":[{"award-number":["Grant Nos. 82372884, 82573758, 2022hwyq29 to H.S., 82372644 to F.Y., 82120108012 and 81930086 to B.S."]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Fund of Fudan University and Cao\u2019ejiang Basic Research","award":["Grant No. 24FCA02 to H.S."],"award-info":[{"award-number":["Grant No. 24FCA02 to H.S."]}]},{"name":"the Fund of Anhui Province Higher Education Outstanding Young Researcher","award":["Grant No. 2024AH020007 to F.Y."],"award-info":[{"award-number":["Grant No. 2024AH020007 to F.Y."]}]},{"name":"Clinical Research Special Project of Anhui Provincial Department of Science and Technology","award":["202204295107020008 to B.S."],"award-info":[{"award-number":["202204295107020008 to B.S."]}]},{"name":"Research Program of Anhui Provincial Department of Education (B.S.); and the USA NIH","award":["U01 CA274295-04 and R01 CA285997 to M.K."],"award-info":[{"award-number":["U01 CA274295-04 and R01 CA285997 to M.K."]}]},{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["2026ZD0555800 to H.S."],"award-info":[{"award-number":["2026ZD0555800 to H.S."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Although inhibitors of oncogenic KRAS have shown clinical efficacy\n                  <jats:sup>1<\/jats:sup>\n                  , resistance to KRAS inhibition is common\n                  <jats:sup>2<\/jats:sup>\n                  , and its molecular basis remains unclear. Here we show that KRASi-resistant cancer cells sustain mitochondrial bioenergetics through enhanced fatty acid (FA) metabolism, despite suppression of canonical KRAS signaling. Specifically, KRASi-resistant pancreatic cancer cells exploit macropinocytosis to scavenge FA released from adipose tissue, fueling beta-oxidation independently of KRAS-PI3K\u03b1 signaling. This adaptive metabolic program is driven by the adhesion G protein-coupled receptor ADGRB1, which activates non-canonical PI3K\u03b3-PAK1 signaling to stimulate macropinocytosis and maintain metabolic homeostasis under KRASi. Disruption of ADGRB1-PI3K\u03b3 signaling dismantles this metabolic program and restores KRASi sensitivity. This pathway operates across multiple KRAS-mutated cancers and is associated with poor therapeutic response and outcome. These findings offer a promising strategy for overcoming KRASi resistance.\n                <\/jats:p>","DOI":"10.64898\/2026.04.01.715565","type":"posted-content","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T22:40:11Z","timestamp":1775256011000},"source":"Crossref","is-referenced-by-count":0,"title":["Fatty acid scavenging enables cancer escape from KRAS inhibition"],"prefix":"10.64898","author":[{"given":"Zihang","family":"Yuan","sequence":"first","affiliation":[{"name":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China"},{"name":"Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China"},{"name":"MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Lin","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunlan","family":"Wang","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingying","family":"Miao","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Da","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziru","family":"Meng","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gangqi","family":"Wang","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew M","family":"Lowy","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, University of California, San Diego Moores Cancer Center, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Karin","sequence":"additional","affiliation":[{"name":"Center for Metabolic and Liver Diseases, SBP Medical Discovery Institute, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China"},{"name":"MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beicheng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China"},{"name":"MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2344-3886","authenticated-orcid":false,"given":"Hua","family":"Su","sequence":"additional","affiliation":[{"name":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China"},{"name":"Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026040610250730000_2026.04.01.715565v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-020-0068-6"},{"key":"2026040610250730000_2026.04.01.715565v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41417-021-00383-9"},{"key":"2026040610250730000_2026.04.01.715565v1.3","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41575-023-00840-w","article-title":"Therapeutic developments in pancreatic cancer","volume":"21","year":"2024","journal-title":"Nat. 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