{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T18:15:47Z","timestamp":1788372947292,"version":"build-2803163510"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"36","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["none"],"award-info":[{"award-number":["none"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014599","name":"Mark Foundation For Cancer Research","doi-asserted-by":"publisher","award":["none"],"award-info":[{"award-number":["none"]}],"id":[{"id":"10.13039\/100014599","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000011","name":"HHMI","doi-asserted-by":"publisher","award":["None"],"award-info":[{"award-number":["None"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018128","name":"Ludwig Family Foundation","doi-asserted-by":"publisher","award":["None"],"award-info":[{"award-number":["None"]}],"id":[{"id":"10.13039\/100018128","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,8]]},"abstract":"<jats:p>\n                    Oncogenic KRAS mutations exhibit a striking tissue-restricted tropism, occurring with high frequency in pancreatic, colorectal, and lung adenocarcinomas while remaining rare in other lineages. The molecular basis for why these specific tissues are uniquely permissive to KRAS transformation, and how this context shapes therapeutic vulnerabilities, remains poorly defined. Here, we utilized CRISPR-mediated genome engineering to generate endogenous, conditional KRAS-mutant isogenic cell line models across three primary permissive lineages (lung, colon, and pancreas) and the nonpermissive breast lineage. Integrated genome-wide CRISPR fitness screens and comparative transcriptome analyses revealed that KRAS-driven synthetic lethal (SL) dependencies are profoundly shaped by their tissue of origin. Strikingly, we observed minimal overlap in SL hits across lineages, with only three genes shared among the permissive lines, suggesting that the\n                    <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                    oncogene operates through divergent, context-specific genetic networks. Mechanistically, we show that KRAS activation induces a universal MYC-driven metabolic signature, but the specific machinery required to sustain this state is lineage-restricted. We identified a dependency on the diphthamide synthesis pathway to maintain translational fidelity amid a KRAS-induced hypertranslational state. These findings demonstrate that even when driven by the same oncogene, tumors exhibit distinct regulatory landscapes and unique genetic vulnerabilities. Our results provide a framework for developing lineage-aware therapeutic strategies, moving beyond universal KRAS inhibition toward targeted interventions tailored to a tumor\u2019s specific tissue context.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2614664123","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:36:43Z","timestamp":1788370603000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Changes in the transcriptome and synthetic lethal dependencies following\n                    <i>KRAS<\/i>\n                    mutant expression reveal profound tissue specificity"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4870-3624","authenticated-orcid":false,"given":"Timothy D.","family":"Martin","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03vek6s52","id-type":"ROR","asserted-by":"publisher"}],"name":"HHMI, Department of Genetics, Harvard University Medical School","place":["Boston"]},{"id":[{"id":"https:\/\/ror.org\/04b6nzv94","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Genetics, Brigham and Women\u2019s Hospital","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei Yuk","family":"Choi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03vek6s52","id-type":"ROR","asserted-by":"publisher"}],"name":"HHMI, Department of Genetics, Harvard University Medical School","place":["Boston"]},{"id":[{"id":"https:\/\/ror.org\/04b6nzv94","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Genetics, Brigham and Women\u2019s Hospital","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7651-7957","authenticated-orcid":false,"given":"Julia C.","family":"McBride","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03vek6s52","id-type":"ROR","asserted-by":"publisher"}],"name":"HHMI, Department of Genetics, Harvard University Medical School","place":["Boston"]},{"id":[{"id":"https:\/\/ror.org\/04b6nzv94","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Genetics, Brigham and Women\u2019s Hospital","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7923-6283","authenticated-orcid":false,"given":"Stephen J.","family":"Elledge","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03vek6s52","id-type":"ROR","asserted-by":"publisher"}],"name":"HHMI, Department of Genetics, Harvard University Medical School","place":["Boston"]},{"id":[{"id":"https:\/\/ror.org\/04b6nzv94","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Genetics, Brigham and Women\u2019s Hospital","place":["Boston"]},{"id":[{"id":"https:\/\/ror.org\/03vek6s52","id-type":"ROR","asserted-by":"publisher"}],"name":"Program in Virology, Harvard University Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3106"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.02.017"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00671-9"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1694-1"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0027"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.03.017"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.01.013"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.05.006"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.06.061"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2017.08.006"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","unstructured":"O. Popow Baseline expression of c-Myc defines the tissue specificity of oncogenic K-Ras. bioRxiv [Preprint] (2025) https:\/\/doi.org\/10.1101\/2025.07.21.665965 (Accessed 25 July 2025).","DOI":"10.1101\/2025.07.21.665965"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw3472"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(03)00086-X"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.11.052"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205550"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1219580"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.943001"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01621-07"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2013.498"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abg5784"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25523-5"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc1048"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI167651"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00753-3"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2023.11.008"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvy071"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/gtc.12742"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.9.16.1953"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09535"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.03.029"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21736-w"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.02.037"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0554-4"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_4_36_2","doi-asserted-by":"crossref","unstructured":"T. D. Martin M. Y. Choi J. McBride S. J. Elledge Data from \u201cChanges in the Transcriptome and Synthetic Lethal Dependencies Following KRAS Mutant Expression Reveal Profound Tissue-Specificity\u201d. Zenodo. https:\/\/zenodo.org\/records\/22017464. Deposited 19 August 2026.","DOI":"10.64898\/2026.04.30.721990"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2614664123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:37:09Z","timestamp":1788370629000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2614664123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,2]]},"references-count":36,"journal-issue":{"issue":"36","published-print":{"date-parts":[[2026,9,8]]}},"alternative-id":["10.1073\/pnas.2614664123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2614664123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,2]]},"assertion":[{"value":"2026-04-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2614664123"}}