{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T18:15:34Z","timestamp":1793729734382,"version":"4.6.1"},"reference-count":95,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T00:00:00Z","timestamp":1731369600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T00:00:00Z","timestamp":1731369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2022M3A9F3017506"],"award-info":[{"award-number":["2022M3A9F3017506"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2022R1A3B1078084"],"award-info":[{"award-number":["2022R1A3B1078084"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2018R1A5A2025079"],"award-info":[{"award-number":["2018R1A5A2025079"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2022R1I1A1A01066096"],"award-info":[{"award-number":["2022R1I1A1A01066096"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002573","name":"Yonsei University","doi-asserted-by":"publisher","award":["the Yonsei Signature Research Cluster Program of 2023-22- 0012"],"award-info":[{"award-number":["the Yonsei Signature Research Cluster Program of 2023-22- 0012"]}],"id":[{"id":"10.13039\/501100002573","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008005","name":"Yonsei University | Yonsei University College of Medicine","doi-asserted-by":"publisher","award":["the Brain Korea 21 FOUR Project for Medical Science"],"award-info":[{"award-number":["the Brain Korea 21 FOUR Project for Medical Science"]}],"id":[{"id":"10.13039\/501100008005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008005","name":"Yonsei University | Yonsei University College of Medicine","doi-asserted-by":"publisher","award":["6-2022-0078"],"award-info":[{"award-number":["6-2022-0078"]}],"id":[{"id":"10.13039\/501100008005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004332","name":"Seoul National University Hospital","doi-asserted-by":"publisher","award":["22B-000-0101"],"award-info":[{"award-number":["22B-000-0101"]}],"id":[{"id":"10.13039\/501100004332","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002648","name":"Catholic University of Korea","doi-asserted-by":"publisher","award":["Basic Medical Science Facilitation Program"],"award-info":[{"award-number":["Basic Medical Science Facilitation Program"]}],"id":[{"id":"10.13039\/501100002648","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002648","name":"Catholic University of Korea","doi-asserted-by":"publisher","award":["5-2023-B0001-00047"],"award-info":[{"award-number":["5-2023-B0001-00047"]}],"id":[{"id":"10.13039\/501100002648","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","award":["a grant of the MD-PhD\/Medical Scientist Training Program"],"award-info":[{"award-number":["a grant of the MD-PhD\/Medical Scientist Training Program"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Biotechnol"],"published-print":{"date-parts":[[2025,9]]},"DOI":"10.1038\/s41587-024-02465-z","type":"journal-article","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T05:02:57Z","timestamp":1731387777000},"page":"1471-1484","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Saturation profiling of drug-resistant genetic variants using prime editing"],"prefix":"10.1038","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8033-4232","authenticated-orcid":false,"given":"Younggwang","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9031-6540","authenticated-orcid":false,"given":"Hyeong-Cheol","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6958-7581","authenticated-orcid":false,"given":"Seungho","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4693-738X","authenticated-orcid":false,"given":"Hyongbum Henry","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,12]]},"reference":[{"key":"2465_CR1","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1016\/S1470-2045(12)70086-4","volume":"13","author":"JC Yang","year":"2012","unstructured":"Yang, J. C. et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 13, 539\u2013548 (2012).","journal-title":"Lancet Oncol."},{"key":"2465_CR2","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1056\/NEJMoa1713137","volume":"378","author":"JC Soria","year":"2018","unstructured":"Soria, J. C. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378, 113\u2013125 (2018).","journal-title":"N. Engl. J. Med."},{"key":"2465_CR3","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.ccr.2006.12.017","volume":"11","author":"C-H Yun","year":"2007","unstructured":"Yun, C.-H. et al. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 11, 217\u2013227 (2007).","journal-title":"Cancer Cell"},{"key":"2465_CR4","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1056\/NEJMoa040938","volume":"350","author":"TJ Lynch","year":"2004","unstructured":"Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129\u20132139 (2004).","journal-title":"N. Engl. J. Med."},{"key":"2465_CR5","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1126\/science.1099314","volume":"304","author":"JG Paez","year":"2004","unstructured":"Paez, J. G. et al. EGFRmutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497\u20131500 (2004).","journal-title":"Science"},{"key":"2465_CR6","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1038\/nrc2088","volume":"7","author":"SV Sharma","year":"2007","unstructured":"Sharma, S. V., Bell, D. W., Settleman, J. & Haber, D. A. Epidermal growth factor receptor mutations in lung cancer. Nat. Rev. Cancer 7, 169\u2013181 (2007).","journal-title":"Nat. Rev. Cancer"},{"key":"2465_CR7","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1038\/s41586-021-03898-1","volume":"597","author":"JP Robichaux","year":"2021","unstructured":"Robichaux, J. P. et al. Structure-based classification predicts drug response in EGFR-mutant NSCLC. Nature 597, 732\u2013737 (2021).","journal-title":"Nature"},{"key":"2465_CR8","doi-asserted-by":"publisher","first-page":"2022","DOI":"10.1016\/j.jtho.2016.06.032","volume":"11","author":"M Campo","year":"2016","unstructured":"Campo, M. et al. Acquired resistance to first-line afatinib and the challenges of prearranged progression biopsies. J. Thorac. Oncol. 11, 2022\u20132026 (2016).","journal-title":"J. Thorac. Oncol."},{"key":"2465_CR9","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1038\/nm.3854","volume":"21","author":"KS Thress","year":"2015","unstructured":"Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560\u2013562 (2015).","journal-title":"Nat. Med."},{"key":"2465_CR10","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1038\/s43018-021-00195-8","volume":"2","author":"A Passaro","year":"2021","unstructured":"Passaro, A., J\u00e4nne, P. A., Mok, T. & Peters, S. Overcoming therapy resistance in EGFR-mutant lung cancer. Nat. Cancer 2, 377\u2013391 (2021).","journal-title":"Nat. Cancer"},{"key":"2465_CR11","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.3390\/ijms20061431","volume":"20","author":"A Russo","year":"2019","unstructured":"Russo, A. et al. Heterogeneous responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with uncommon EGFR mutations: new insights and future perspectives in this complex clinical scenario. Int. J. Mol. Sci. 20, 1431 (2019).","journal-title":"Int. J. Mol. Sci."},{"key":"2465_CR12","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1016\/j.jtho.2020.12.002","volume":"16","author":"A Passaro","year":"2021","unstructured":"Passaro, A. et al. Recent advances on the role of EGFR tyrosine kinase inhibitors in the management of NSCLC with uncommon, non exon 20 insertions, EGFR mutations. J. Thorac. Oncol. 16, 764\u2013773 (2021).","journal-title":"J. Thorac. Oncol."},{"key":"2465_CR13","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1016\/j.jtho.2019.12.126","volume":"15","author":"JC Yang","year":"2020","unstructured":"Yang, J. C. et al. Afatinib for the treatment of NSCLC harboring uncommon EGFR mutations: a database of 693 cases. J. Thorac. Oncol. 15, 803\u2013815 (2020).","journal-title":"J. Thorac. Oncol."},{"key":"2465_CR14","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.annonc.2022.02.225","volume":"33","author":"M Janning","year":"2022","unstructured":"Janning, M. et al. Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM). Ann. Oncol. 33, 602\u2013615 (2022).","journal-title":"Ann. Oncol."},{"key":"2465_CR15","doi-asserted-by":"publisher","first-page":"8878","DOI":"10.3390\/ijms24108878","volume":"24","author":"G Pretelli","year":"2023","unstructured":"Pretelli, G., Spagnolo, C. C., Ciappina, G., Santarpia, M. & Pasello, G. Overview on therapeutic options in uncommon EGFR mutant non-small cell lung cancer (NSCLC): new lights for an unmet medical need. Int. J. Mol. Sci. 24, 8878 (2023).","journal-title":"Int. J. Mol. Sci."},{"key":"2465_CR16","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1126\/scitranslmed.aan6566","volume":"9","author":"S Kohsaka","year":"2017","unstructured":"Kohsaka, S. et al. A method of high-throughput functional evaluation of EGFR gene variants of unknown significance in cancer. Sci. Transl. Med. 9, 416 (2017).","journal-title":"Sci. Transl. Med."},{"key":"2465_CR17","doi-asserted-by":"publisher","first-page":"9377","DOI":"10.1074\/jbc.RA118.006336","volume":"294","author":"D Chakroborty","year":"2019","unstructured":"Chakroborty, D. et al. An unbiased in vitro screen for activating epidermal growth factor receptor mutations. J. Biol. Chem. 294, 9377\u20139389 (2019).","journal-title":"J. Biol. Chem."},{"key":"2465_CR18","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.trsl.2022.11.002","volume":"255","author":"L An","year":"2023","unstructured":"An, L. et al. Defining the sensitivity landscape of EGFR variants to tyrosine kinase inhibitors. Transl. Res. 255, 14\u201325 (2023).","journal-title":"Transl. Res."},{"key":"2465_CR19","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1038\/nature24644","volume":"551","author":"NM Gaudelli","year":"2017","unstructured":"Gaudelli, N. M. et al. Programmable base editing of A\u2022T to G\u2022C in genomic DNA without DNA cleavage. Nature 551, 464\u2013471 (2017).","journal-title":"Nature"},{"key":"2465_CR20","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1038\/nature17946","volume":"533","author":"AC Komor","year":"2016","unstructured":"Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A. & Liu, D. R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420\u2013424 (2016).","journal-title":"Nature"},{"key":"2465_CR21","doi-asserted-by":"publisher","first-page":"aaf8729","DOI":"10.1126\/science.aaf8729","volume":"353","author":"K Nishida","year":"2016","unstructured":"Nishida, K. et al. Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems. Science 353, aaf8729 (2016).","journal-title":"Science"},{"key":"2465_CR22","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1038\/s41586-019-1711-4","volume":"576","author":"AV Anzalone","year":"2019","unstructured":"Anzalone, A. V. et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 576, 149\u2013157 (2019).","journal-title":"Nature"},{"key":"2465_CR23","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/s41586-018-0461-z","volume":"562","author":"GM Findlay","year":"2018","unstructured":"Findlay, G. M. et al. Accurate classification of BRCA1 variants with saturation genome editing. Nature 562, 217\u2013222 (2018).","journal-title":"Nature"},{"key":"2465_CR24","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1016\/j.ajhg.2020.10.015","volume":"107","author":"I Meitlis","year":"2020","unstructured":"Meitlis, I. et al. Multiplexed functional assessment of genetic variants in CARD11. Am. J. Hum. Genet. 107, 1029\u20131043 (2020).","journal-title":"Am. J. Hum. Genet."},{"key":"2465_CR25","doi-asserted-by":"publisher","first-page":"1446","DOI":"10.1038\/s41588-024-01800-z","volume":"56","author":"M Buckley","year":"2024","unstructured":"Buckley, M. et al. Saturation genome editing maps the functional spectrum of pathogenic VHL alleles. Nat. Genet. 56, 1446\u20131455 (2024).","journal-title":"Nat. Genet."},{"key":"2465_CR26","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1016\/j.cell.2021.01.012","volume":"184","author":"RE Hanna","year":"2021","unstructured":"Hanna, R. E. et al. Massively parallel assessment of human variants with base editor screens. Cell 184, 1064\u20131080 (2021).","journal-title":"Cell"},{"key":"2465_CR27","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1016\/j.cell.2021.01.041","volume":"184","author":"R Cuella-Martin","year":"2021","unstructured":"Cuella-Martin, R. et al. Functional interrogation of DNA damage response variants with base editing screens. Cell 184, 1081\u20131097 (2021).","journal-title":"Cell"},{"key":"2465_CR28","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1038\/s41587-022-01276-4","volume":"40","author":"Y Kim","year":"2022","unstructured":"Kim, Y. et al. High-throughput functional evaluation of human cancer-associated mutations using base editors. Nat. Biotechnol. 40, 874\u2013884 (2022).","journal-title":"Nat. Biotechnol."},{"key":"2465_CR29","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1038\/s41587-021-01172-3","volume":"40","author":"FJ Sanchez-Rivera","year":"2022","unstructured":"Sanchez-Rivera, F. J. et al. Base editing sensor libraries for high-throughput engineering and functional analysis of cancer-associated single nucleotide variants. Nat. Biotechnol. 40, 862\u2013873 (2022).","journal-title":"Nat. Biotechnol."},{"key":"2465_CR30","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1038\/s41586-023-05755-9","volume":"615","author":"F Perner","year":"2023","unstructured":"Perner, F. et al. MEN1 mutations mediate clinical resistance to menin inhibition. Nature 615, 913\u2013919 (2023).","journal-title":"Nature"},{"key":"2465_CR31","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1038\/s41587-021-01201-1","volume":"40","author":"S Erwood","year":"2022","unstructured":"Erwood, S. et al. Saturation variant interpretation using CRISPR prime editing. Nat. Biotechnol. 40, 885\u2013895 (2022).","journal-title":"Nat. Biotechnol."},{"key":"2465_CR32","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1038\/nature13695","volume":"513","author":"GM Findlay","year":"2014","unstructured":"Findlay, G. M., Boyle, E. A., Hause, R. J., Klein, J. C. & Shendure, J. Saturation editing of genomic regions by multiplex homology-directed repair. Nature 513, 120\u2013123 (2014).","journal-title":"Nature"},{"key":"2465_CR33","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-43041-4","volume":"14","author":"EJ Radford","year":"2023","unstructured":"Radford, E. J. et al. Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation. Nat. Commun. 14, 7702 (2023).","journal-title":"Nat. Commun."},{"key":"2465_CR34","doi-asserted-by":"publisher","unstructured":"Huang, H. et al. Saturation genome editing-based functional evaluation and clinical classification of BRCA2 single nucleotide variants. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/2023.12.14.571597 (2023).","DOI":"10.1101\/2023.12.14.571597"},{"key":"2465_CR35","doi-asserted-by":"publisher","first-page":"5635","DOI":"10.1016\/j.cell.2021.09.018","volume":"184","author":"PJ Chen","year":"2021","unstructured":"Chen, P. J. et al. Enhanced prime editing systems by manipulating cellular determinants of editing outcomes. Cell 184, 5635\u20135652 (2021).","journal-title":"Cell"},{"key":"2465_CR36","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29339-9","volume":"13","author":"X Li","year":"2022","unstructured":"Li, X. et al. Highly efficient prime editing by introducing same-sense mutations in pegRNA or stabilizing its structure. Nat. Commun. 13, 1669 (2022).","journal-title":"Nat. Commun."},{"key":"2465_CR37","doi-asserted-by":"publisher","first-page":"2256","DOI":"10.1016\/j.cell.2023.03.034","volume":"186","author":"G Yu","year":"2023","unstructured":"Yu, G. et al. Prediction of efficiencies for diverse prime editing systems in multiple cell types. Cell 186, 2256\u20132272 (2023).","journal-title":"Cell"},{"key":"2465_CR38","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/nrg.2017.117","volume":"19","author":"JJ Salk","year":"2018","unstructured":"Salk, J. J., Schmitt, M. W. & Loeb, L. A. Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations. Nat. Rev. Genet. 19, 269\u2013285 (2018).","journal-title":"Nat. Rev. Genet."},{"key":"2465_CR39","doi-asserted-by":"publisher","DOI":"10.1093\/nargab\/lqab019","volume":"3","author":"N Stoler","year":"2021","unstructured":"Stoler, N. & Nekrutenko, A. Sequencing error profiles of Illumina sequencing instruments. NAR Genom. Bioinform. 3, lqab019 (2021).","journal-title":"NAR Genom. Bioinform."},{"key":"2465_CR40","unstructured":"Broad Institute of Harvard and MIT. DepMap: the cancer dependency map project at Broad Institute. DepMap https:\/\/depmap.org\/portal\/ (2020)."},{"key":"2465_CR41","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.1016\/j.cell.2015.11.015","volume":"163","author":"T Hart","year":"2015","unstructured":"Hart, T. et al. High-Resolution CRISPR screens reveal fitness genes and genotype-specific cancer liabilities. Cell 163, 1515\u20131526 (2015).","journal-title":"Cell"},{"key":"2465_CR42","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/nbt.3437","volume":"34","author":"JG Doench","year":"2016","unstructured":"Doench, J. G. et al. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR\u2013Cas9. Nat. Biotechnol. 34, 184\u2013191 (2016).","journal-title":"Nat. Biotechnol."},{"key":"2465_CR43","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/nrg.2017.97","volume":"19","author":"JG Doench","year":"2018","unstructured":"Doench, J. G. Am I ready for CRISPR? A user\u2019s guide to genetic screens. Nat. Rev. Genet. 19, 67\u201380 (2018).","journal-title":"Nat. Rev. Genet."},{"key":"2465_CR44","doi-asserted-by":"publisher","first-page":"4633","DOI":"10.1016\/j.molcel.2023.11.021","volume":"83","author":"X Ren","year":"2023","unstructured":"Ren, X. et al. High-throughput PRIME-editing screens identify functional DNA variants in the human genome. Mol. Cell 83, 4633\u20134645 (2023).","journal-title":"Mol. Cell"},{"key":"2465_CR45","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-024-02172-9","author":"SI Gould","year":"2024","unstructured":"Gould, S. I. et al. High-throughput evaluation of genetic variants with prime editing sensor libraries. Nat. Biotechnol. https:\/\/doi.org\/10.1038\/s41587-024-02172-9 (2024).","journal-title":"Nat. Biotechnol."},{"key":"2465_CR46","doi-asserted-by":"publisher","unstructured":"Chardon, F. M. et al. A multiplex, prime editing framework for identifying drug resistance variants at scale. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/2023.07.27.550902 (2023).","DOI":"10.1101\/2023.07.27.550902"},{"key":"2465_CR47","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0554-4","volume":"15","author":"W Li","year":"2014","unstructured":"Li, W. et al. MAGeCK enables robust identification of essential genes from genome-scale CRISPR\/Cas9 knockout screens. Genome Biol. 15, 554 (2014).","journal-title":"Genome Biol."},{"key":"2465_CR48","doi-asserted-by":"publisher","first-page":"2240","DOI":"10.1158\/1078-0432.CCR-12-2246","volume":"19","author":"HA Yu","year":"2013","unstructured":"Yu, H. A. et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin. Cancer Res. 19, 2240\u20132247 (2013).","journal-title":"Clin. Cancer Res."},{"key":"2465_CR49","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1056\/NEJMoa1612674","volume":"376","author":"TS Mok","year":"2016","unstructured":"Mok, T. S. et al. Osimertinib or platinum\u2013pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med. 376, 629\u2013640 (2016).","journal-title":"N. Engl. J. Med."},{"key":"2465_CR50","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0778-0","volume":"17","author":"C-S Tan","year":"2018","unstructured":"Tan, C.-S. et al. Third generation EGFR TKIs: current data and future directions. Mol. Cancer 17, 29 (2018).","journal-title":"Mol. Cancer"},{"key":"2465_CR51","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1158\/1535-7163.MCT-16-0407","volume":"16","author":"Y Kobayashi","year":"2017","unstructured":"Kobayashi, Y. et al. Characterization of EGFR T790M, L792F, and C797S mutations as mechanisms of acquired resistance to afatinib in lung cancer. Mol. Cancer Ther. 16, 357\u2013364 (2017).","journal-title":"Mol. Cancer Ther."},{"key":"2465_CR52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.lungcan.2018.01.015","volume":"118","author":"Y Liu","year":"2018","unstructured":"Liu, Y. et al. Acquired EGFR L718V mutation mediates resistance to osimertinib in non-small cell lung cancer but retains sensitivity to afatinib. Lung Cancer 118, 1\u20135 (2018).","journal-title":"Lung Cancer"},{"key":"2465_CR53","doi-asserted-by":"publisher","first-page":"3097","DOI":"10.1158\/1078-0432.CCR-17-2310","volume":"24","author":"Z Yang","year":"2018","unstructured":"Yang, Z. et al. Investigating novel resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer patients. Clin. Cancer Res. 24, 3097\u20133107 (2018).","journal-title":"Clin. Cancer Res."},{"key":"2465_CR54","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1007\/s12672-022-00537-7","volume":"13","author":"M Li","year":"2022","unstructured":"Li, M. et al. L718Q\/V mutation in exon 18 of EGFR mediates resistance to osimertinib: clinical features and treatment. Discov. Oncol. 13, 72 (2022).","journal-title":"Discov. Oncol."},{"key":"2465_CR55","doi-asserted-by":"publisher","first-page":"3873","DOI":"10.1002\/cam4.3929","volume":"10","author":"N Sueoka-Aragane","year":"2021","unstructured":"Sueoka-Aragane, N. et al. The role of comprehensive analysis with circulating tumor DNA in advanced non-small cell lung cancer patients considered for osimertinib treatment. Cancer Med. 10, 3873\u20133885 (2021).","journal-title":"Cancer Med."},{"key":"2465_CR56","doi-asserted-by":"publisher","first-page":"2941","DOI":"10.21873\/invivo.12586","volume":"35","author":"DE Carlo","year":"2021","unstructured":"Carlo, D. E. et al. Acquired EGFR C797G mutation detected by liquid biopsy as resistance mechanism after treatment with osimertinib: a case report. In Vivo 35, 2941\u20132945 (2021).","journal-title":"In Vivo"},{"key":"2465_CR57","doi-asserted-by":"publisher","first-page":"9010353","DOI":"10.1155\/2018\/9010353","volume":"2018","author":"K Nie","year":"2018","unstructured":"Nie, K. et al. Mutational profiling of non-small-cell lung cancer resistant to osimertinib using next-generation sequencing in chinese patients. BioMed Res. Int. 2018, 9010353 (2018).","journal-title":"BioMed Res. Int."},{"key":"2465_CR58","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1042\/BJ20080728","volume":"415","author":"E Avizienyte","year":"2008","unstructured":"Avizienyte, E., Ward, R. A. & Garner, A. P. Comparison of the EGFR resistance mutation profiles generated by EGFR-targeted tyrosine kinase inhibitors and the impact of drug combinations. Biochem. J. 415, 197\u2013206 (2008).","journal-title":"Biochem. J."},{"key":"2465_CR59","doi-asserted-by":"publisher","first-page":"7519","DOI":"10.1158\/1078-0432.CCR-08-0151","volume":"14","author":"J Bean","year":"2008","unstructured":"Bean, J. et al. Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin. Cancer Res. 14, 7519\u20137525 (2008).","journal-title":"Clin. Cancer Res."},{"key":"2465_CR60","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.cllc.2021.12.008","volume":"23","author":"L Zhang","year":"2022","unstructured":"Zhang, L. et al. Molecular characteristics of the uncommon EGFR exon 21 T854A mutation and response to osimertinib in patients with non-small cell lung cancer. Clin. Lung Cancer 23, 311\u2013319 (2022).","journal-title":"Clin. Lung Cancer"},{"key":"2465_CR61","doi-asserted-by":"publisher","first-page":"6812","DOI":"10.1111\/jcmm.14565","volume":"23","author":"P Xing","year":"2019","unstructured":"Xing, P. et al. Co-mutational assessment of circulating tumour DNA (ctDNA) during osimertinib treatment for T790M mutant lung cancer. J. Cell. Mol. Med. 23, 6812\u20136821 (2019).","journal-title":"J. Cell. Mol. Med."},{"key":"2465_CR62","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2206588119","volume":"119","author":"BP Brown","year":"2022","unstructured":"Brown, B. P. et al. Allele-specific activation, enzyme kinetics, and inhibitor sensitivities of EGFR exon 19 deletion mutations in lung cancer. Proc. Natl Acad. Sci. USA 119, e2206588119 (2022).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2465_CR63","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1080\/14737159.2017.1288568","volume":"17","author":"U Malapelle","year":"2017","unstructured":"Malapelle, U. et al. Profile of the Roche cobas\u00ae EGFR mutation test v2 for non-small cell lung cancer. Expert Rev. Mol. Diagn. 17, 209\u2013215 (2017).","journal-title":"Expert Rev. Mol. Diagn."},{"key":"2465_CR64","doi-asserted-by":"publisher","first-page":"10417","DOI":"10.1158\/0008-5472.CAN-07-1248","volume":"67","author":"Z Yu","year":"2007","unstructured":"Yu, Z. et al. Resistance to an irreversible epidermal growth factor receptor (EGFR) inhibitor in EGFR-mutant lung cancer reveals novel treatment strategies. Cancer Res. 67, 10417\u201310427 (2007).","journal-title":"Cancer Res."},{"key":"2465_CR65","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1016\/j.cell.2006.05.013","volume":"125","author":"X Zhang","year":"2006","unstructured":"Zhang, X., Gureasko, J., Shen, K., Cole, P. A. & Kuriyan, J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125, 1137\u20131149 (2006).","journal-title":"Cell"},{"key":"2465_CR66","doi-asserted-by":"publisher","first-page":"7351","DOI":"10.1158\/1078-0432.CCR-17-1745","volume":"23","author":"Y Hu","year":"2017","unstructured":"Hu, Y. et al. Discrimination of germline EGFR T790M mutations in plasma cell-free DNA allows study of prevalence across 31,414 cancer patients. Clin. Cancer Res. 23, 7351\u20137359 (2017).","journal-title":"Clin. Cancer Res."},{"key":"2465_CR67","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1038\/s41416-019-0573-8","volume":"121","author":"A Leonetti","year":"2019","unstructured":"Leonetti, A. et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br. J. Cancer 121, 725\u2013737 (2019).","journal-title":"Br. J. Cancer"},{"key":"2465_CR68","doi-asserted-by":"publisher","first-page":"3341","DOI":"10.1158\/1078-0432.CCR-18-3829","volume":"25","author":"BP Brown","year":"2019","unstructured":"Brown, B. P. et al. On-target resistance to the mutant-selective EGFR inhibitor osimertinib can develop in an allele-specific manner dependent on the original EGFR-activating mutation. Clin. Cancer Res. 25, 3341\u20133351 (2019).","journal-title":"Clin. Cancer Res."},{"key":"2465_CR69","first-page":"100193","volume":"2","author":"Y Wei","year":"2021","unstructured":"Wei, Y. et al. Afatinib as a potential therapeutic option for patients with NSCLC with EGFR G724S. JTO Clin. Res. Rep. 2, 100193 (2021).","journal-title":"JTO Clin. Res. Rep."},{"key":"2465_CR70","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1016\/j.jtho.2018.05.024","volume":"13","author":"Q Zhang","year":"2018","unstructured":"Zhang, Q. et al. EGFR L792H and G796R: two novel mutations mediating resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib. J. Thorac. Oncol. 13, 1415\u20131421 (2018).","journal-title":"J. Thorac. Oncol."},{"key":"2465_CR71","first-page":"241","volume":"8","author":"SJ Klempner","year":"2017","unstructured":"Klempner, S. J., Mehta, P., Schrock, A. B., Ali, S. M. & Ou, S. I. cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature. Lung Cancer 8, 241\u2013247 (2017).","journal-title":"Lung Cancer"},{"key":"2465_CR72","doi-asserted-by":"publisher","first-page":"49671","DOI":"10.18632\/oncotarget.17913","volume":"8","author":"D Zheng","year":"2017","unstructured":"Zheng, D. et al. EGFR G796D mutation mediates resistance to osimertinib. Oncotarget 8, 49671\u201349679 (2017).","journal-title":"Oncotarget"},{"key":"2465_CR73","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1146\/annurev-biochem-071320-112701","volume":"90","author":"Y Liu","year":"2021","unstructured":"Liu, Y., Yang, Q. & Zhao, F. Synonymous but not silent: the codon usage code for gene expression and protein folding. Annu. Rev. Biochem. 90, 375\u2013401 (2021).","journal-title":"Annu. Rev. Biochem."},{"key":"2465_CR74","doi-asserted-by":"publisher","DOI":"10.1016\/j.canep.2021.102080","volume":"76","author":"T John","year":"2022","unstructured":"John, T. et al. Uncommon EGFR mutations in non-small-cell lung cancer: a systematic literature review of prevalence and clinical outcomes. Cancer Epidemiol. 76, 102080 (2022).","journal-title":"Cancer Epidemiol."},{"key":"2465_CR75","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-024-02268-2","author":"N Mathis","year":"2024","unstructured":"Mathis, N. et al. Machine learning prediction of prime editing efficiency across diverse chromatin contexts. Nat. Biotechnol. https:\/\/doi.org\/10.1038\/s41587-024-02268-2 (2024).","journal-title":"Nat. Biotechnol."},{"key":"2465_CR76","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1038\/s41587-021-01039-7","volume":"40","author":"JW Nelson","year":"2022","unstructured":"Nelson, J. W. et al. Engineered pegRNAs improve prime editing efficiency. Nat. Biotechnol. 40, 402\u2013410 (2022).","journal-title":"Nat. Biotechnol."},{"key":"2465_CR77","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.ijar.2007.03.011","volume":"47","author":"S Mantaci","year":"2008","unstructured":"Mantaci, S., Restivo, A. & Sciortino, M. Distance measures for biological sequences: some recent approaches. Int. J. Approx. Reason. 47, 109\u2013124 (2008).","journal-title":"Int. J. Approx. Reason."},{"key":"2465_CR78","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1038\/nmeth.4104","volume":"14","author":"HK Kim","year":"2017","unstructured":"Kim, H. K. et al. In vivo high-throughput profiling of CRISPR\u2013Cpf1 activity. Nat. Methods 14, 153\u2013159 (2017).","journal-title":"Nat. Methods"},{"key":"2465_CR79","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-015-0846-3","volume":"16","author":"Y Dang","year":"2015","unstructured":"Dang, Y. et al. Optimizing sgRNA structure to improve CRISPR\u2013Cas9 knockout efficiency. Genome Biol. 16, 280 (2015).","journal-title":"Genome Biol."},{"key":"2465_CR80","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1038\/nmeth.3047","volume":"11","author":"NE Sanjana","year":"2014","unstructured":"Sanjana, N. E., Shalem, O. & Zhang, F. Improved vectors and genome-wide libraries for CRISPR screening. Nat. Methods 11, 783\u2013784 (2014).","journal-title":"Nat. Methods"},{"key":"2465_CR81","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/s41587-020-0412-8","volume":"38","author":"SM Miller","year":"2020","unstructured":"Miller, S. M. et al. Continuous evolution of SpCas9 variants compatible with non-G PAMs. Nat. Biotechnol. 38, 471\u2013481 (2020).","journal-title":"Nat. Biotechnol."},{"key":"2465_CR82","doi-asserted-by":"publisher","first-page":"e117","DOI":"10.1093\/nar\/gks624","volume":"40","author":"AW Briggs","year":"2012","unstructured":"Briggs, A. W. et al. Iterative capped assembly: rapid and scalable synthesis of repeat-module DNA such as TAL effectors from individual monomers. Nucleic Acids Res. 40, e117 (2012).","journal-title":"Nucleic Acids Res."},{"key":"2465_CR83","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1355-3","volume":"18","author":"S Kim","year":"2017","unstructured":"Kim, S., Bae, T., Hwang, J. & Kim, J. S. Rescue of high-specificity Cas9 variants using sgRNAs with matched 5\u2032 nucleotides. Genome Biol. 18, 218 (2017).","journal-title":"Genome Biol."},{"key":"2465_CR84","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1093\/bioinformatics\/btw561","volume":"33","author":"J Park","year":"2017","unstructured":"Park, J., Lim, K., Kim, J. S. & Bae, S. Cas-analyzer: an online tool for assessing genome editing results using NGS data. Bioinformatics 33, 286\u2013288 (2017).","journal-title":"Bioinformatics"},{"key":"2465_CR85","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1038\/nbt.4172","volume":"36","author":"LW Koblan","year":"2018","unstructured":"Koblan, L. W. et al. Improving cytidine and adenine base editors by expression optimization and ancestral reconstruction. Nat. Biotechnol. 36, 843\u2013846 (2018).","journal-title":"Nat. Biotechnol."},{"key":"2465_CR86","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1016\/j.molcel.2015.05.016","volume":"58","author":"D Heckl","year":"2015","unstructured":"Heckl, D. & Charpentier, E. Toward whole-transcriptome editing with CRISPR\u2013Cas9. Mol. Cell 58, 560\u2013562 (2015).","journal-title":"Mol. Cell"},{"key":"2465_CR87","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1126\/science.1247005","volume":"343","author":"O Shalem","year":"2014","unstructured":"Shalem, O. et al. Genome-scale CRISPR\u2013Cas9 knockout screening in human cells. Science 343, 84\u201387 (2014).","journal-title":"Science"},{"key":"2465_CR88","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1038\/s41587-020-0600-6","volume":"39","author":"PC DeWeirdt","year":"2021","unstructured":"DeWeirdt, P. C. et al. Optimization of AsCas12a for combinatorial genetic screens in human cells. Nat. Biotechnol. 39, 94\u2013104 (2021).","journal-title":"Nat. Biotechnol."},{"key":"2465_CR89","doi-asserted-by":"publisher","first-page":"7989","DOI":"10.1093\/nar\/gkz487","volume":"47","author":"W Chen","year":"2019","unstructured":"Chen, W. et al. Massively parallel profiling and predictive modeling of the outcomes of CRISPR\/Cas9-mediated double-strand break repair. Nucleic Acids Res. 47, 7989\u20138003 (2019).","journal-title":"Nucleic Acids Res."},{"key":"2465_CR90","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","volume":"2","author":"E Cerami","year":"2012","unstructured":"Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401\u2013404 (2012).","journal-title":"Cancer Discov."},{"key":"2465_CR91","doi-asserted-by":"publisher","first-page":"D1210","DOI":"10.1093\/nar\/gkad986","volume":"52","author":"Z Sondka","year":"2024","unstructured":"Sondka, Z. et al. COSMIC: a curated database of somatic variants and clinical data for cancer. Nucleic Acids Res. 52, D1210\u2013D1217 (2024).","journal-title":"Nucleic Acids Res."},{"key":"2465_CR92","doi-asserted-by":"publisher","first-page":"497","DOI":"10.6004\/jnccn.2022.0025","volume":"20","author":"DS Ettinger","year":"2022","unstructured":"Ettinger, D. S. et al. Non-small cell lung cancer, version 3.2022, NCCN clinical practice guidelines in oncology. J. Natl Compr. Canc. Netw. 20, 497\u2013530 (2022).","journal-title":"J. Natl Compr. Canc. Netw."},{"key":"2465_CR93","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-02174-1","volume":"21","author":"E Ten Hacken","year":"2020","unstructured":"Ten Hacken, E. et al. High throughput single-cell detection of multiplex CRISPR-edited gene modifications. Genome Biol. 21, 266 (2020).","journal-title":"Genome Biol."},{"key":"2465_CR94","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1158\/2159-8290.CD-14-0337","volume":"4","author":"DA Cross","year":"2014","unstructured":"Cross, D. A. et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 4, 1046\u20131061 (2014).","journal-title":"Cancer Discov."},{"key":"2465_CR95","doi-asserted-by":"publisher","first-page":"eabg6428","DOI":"10.1126\/scitranslmed.abg6428","volume":"13","author":"KR Zhang","year":"2021","unstructured":"Zhang, K. R. et al. Targeting AKR1B1 inhibits glutathione de novo synthesis to overcome acquired resistance to EGFR-targeted therapy in lung cancer. Sci. Transl. Med. 13, eabg6428 (2021).","journal-title":"Sci. Transl. Med."}],"container-title":["Nature Biotechnology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41587-024-02465-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41587-024-02465-z","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41587-024-02465-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T06:01:58Z","timestamp":1758088918000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41587-024-02465-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,12]]},"references-count":95,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["2465"],"URL":"https:\/\/doi.org\/10.1038\/s41587-024-02465-z","relation":{},"ISSN":["1087-0156","1546-1696"],"issn-type":[{"value":"1087-0156","type":"print"},{"value":"1546-1696","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,12]]},"assertion":[{"value":"4 July 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 October 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 November 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Yonsei University has filed a patent application based on this work, in which Y.K., H.C.O., S.L. and H.H.K. are listed as inventors. H.H.K is the founder of LiquidCRISPR.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}