{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T19:11:35Z","timestamp":1791141095499,"version":"4.1.0"},"reference-count":78,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T00:00:00Z","timestamp":1719446400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T00:00:00Z","timestamp":1719446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004097","name":"Fondation ARC pour la Recherche sur le Cancer","doi-asserted-by":"publisher","award":["PJA2"],"award-info":[{"award-number":["PJA2"]}],"id":[{"id":"10.13039\/501100004097","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["DEQ20170839117"],"award-info":[{"award-number":["DEQ20170839117"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["DEQ20170839117"],"award-info":[{"award-number":["DEQ20170839117"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["DEQ20170839117"],"award-info":[{"award-number":["DEQ20170839117"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["Inserm"],"award-info":[{"award-number":["Inserm"]}],"id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["Inserm"],"award-info":[{"award-number":["Inserm"]}],"id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fondation Toulouse Cancer Sant\u00e9 (FTCS), Labex TOUCAN, ALK+ &ROS1 France patient association (donation), Kura Oncology"},{"DOI":"10.13039\/501100006364","name":"Institut National Du Cancer","doi-asserted-by":"publisher","award":["PRT-K18-048"],"award-info":[{"award-number":["PRT-K18-048"]}],"id":[{"id":"10.13039\/501100006364","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004099","name":"Ligue Contre le Cancer","doi-asserted-by":"publisher","award":["LNCC"],"award-info":[{"award-number":["LNCC"]}],"id":[{"id":"10.13039\/501100004099","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Drug-tolerance has emerged as one of the major non-genetic adaptive processes driving resistance to targeted therapy (TT) in non-small cell lung cancer (NSCLC). However, the kinetics and sequence of molecular events governing this adaptive response remain poorly understood. Here, we combine real-time monitoring of the cell-cycle dynamics and single-cell RNA sequencing in a broad panel of oncogenic addiction such as EGFR-, ALK-, BRAF- and KRAS-mutant NSCLC, treated with their corresponding TT. We identify a common path of drug\u00a0adaptation, which invariably involves alveolar type 1 (AT1) differentiation and Rho-associated protein kinase (ROCK)-mediated cytoskeletal remodeling. We also isolate and characterize a rare population of early escapers, which represent the earliest resistance-initiating cells that emerge in the first hours of treatment from the AT1-like population. A phenotypic drug screen identify farnesyltransferase inhibitors (FTI) such as tipifarnib as the most effective drugs in preventing relapse to TT in vitro and in vivo in several models of oncogenic addiction, which is confirmed by genetic depletion of the farnesyltransferase. These findings pave the way for the development of treatments combining TT and FTI to effectively prevent tumor relapse in oncogene-addicted NSCLC patients.<\/jats:p>","DOI":"10.1038\/s41467-024-49360-4","type":"journal-article","created":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T06:03:09Z","timestamp":1719468189000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Farnesyltransferase inhibition overcomes oncogene-addicted non-small cell lung cancer adaptive resistance to targeted therapies"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3863-563X","authenticated-orcid":false,"given":"Sarah","family":"Figarol","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7966-5597","authenticated-orcid":false,"given":"C\u00e9lia","family":"Delahaye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00e9mi","family":"Gence","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lia","family":"Doussine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3032-3180","authenticated-orcid":false,"given":"Juan Pablo","family":"Cerapio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathylda","family":"Brachais","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudine","family":"Tardy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2643-3897","authenticated-orcid":false,"given":"Nicolas","family":"B\u00e9ry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghda","family":"Asslan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2466-4824","authenticated-orcid":false,"given":"Jacques","family":"Colinge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Philippe","family":"Villemin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5527-5680","authenticated-orcid":false,"given":"Antonio","family":"Maraver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2748-2607","authenticated-orcid":false,"given":"Irene","family":"Ferrer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Paz-Ares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Kessler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Burrows","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Lajoie-Mazenc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Dongay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Morin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Am\u00e9lie","family":"Florent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1758-3233","authenticated-orcid":false,"given":"Sandra","family":"Pagano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estelle","family":"Taranchon-Clermont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Casanova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Pradines","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5921-7613","authenticated-orcid":false,"given":"Julien","family":"Mazieres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2344-1883","authenticated-orcid":false,"given":"Gilles","family":"Favre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0908-8323","authenticated-orcid":false,"given":"Olivier","family":"Calvayrac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,27]]},"reference":[{"key":"49360_CR1","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":"49360_CR2","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/S1470-2045(11)70393-X","volume":"13","author":"R Rosell","year":"2012","unstructured":"Rosell, R. et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 13, 239\u2013246 (2012).","journal-title":"Lancet Oncol."},{"key":"49360_CR3","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/S1470-2045(15)00488-X","volume":"17","author":"AT Shaw","year":"2016","unstructured":"Shaw, A. T. et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. 17, 234\u2013242 (2016).","journal-title":"Lancet Oncol."},{"key":"49360_CR4","doi-asserted-by":"publisher","first-page":"2018","DOI":"10.1056\/NEJMoa2027187","volume":"383","author":"AT Shaw","year":"2020","unstructured":"Shaw, A. T. et al. First-Line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N. Engl. J. Med. 383, 2018\u20132029 (2020).","journal-title":"N. Engl. J. Med."},{"key":"49360_CR5","doi-asserted-by":"publisher","first-page":"1963","DOI":"10.1056\/NEJMoa1406766","volume":"371","author":"AT Shaw","year":"2014","unstructured":"Shaw, A. T. et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N. Engl. J. Med. 371, 1963\u20131971 (2014).","journal-title":"N. Engl. J. Med."},{"key":"49360_CR6","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1016\/S1470-2045(19)30655-2","volume":"20","author":"AT Shaw","year":"2019","unstructured":"Shaw, A. T. et al. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 20, 1691\u20131701 (2019).","journal-title":"Lancet Oncol."},{"key":"49360_CR7","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1056\/NEJMoa2112431","volume":"386","author":"BT Li","year":"2022","unstructured":"Li, B. T. et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N. Engl. J. Med. 386, 241\u2013251 (2022).","journal-title":"N. Engl. J. Med."},{"key":"49360_CR8","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1016\/S1470-2045(17)30679-4","volume":"18","author":"D Planchard","year":"2017","unstructured":"Planchard, D. et al. Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 18, 1307\u20131316 (2017).","journal-title":"Lancet Oncol."},{"key":"49360_CR9","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1056\/NEJMoa2004407","volume":"383","author":"PK Paik","year":"2020","unstructured":"Paik, P. K. et al. Tepotinib in non-small-cell lung cancer with MET Exon 14 skipping mutations. N. Engl. J. Med. 383, 931\u2013943 (2020).","journal-title":"N. Engl. J. Med."},{"key":"49360_CR10","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1016\/S0140-6736(23)00221-0","volume":"401","author":"AJ de Langen","year":"2023","unstructured":"de Langen, A. J. et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS(G12C) mutation: a randomised, open-label, phase 3 trial. Lancet 401, 733\u2013746 (2023).","journal-title":"Lancet"},{"key":"49360_CR11","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1056\/NEJMoa2204619","volume":"387","author":"PA Janne","year":"2022","unstructured":"Janne, P. A. et al. Adagrasib in non-small-cell lung cancer harboring a KRAS(G12C) mutation. N. Engl. J. Med. 387, 120\u2013131 (2022).","journal-title":"N. Engl. J. Med."},{"key":"49360_CR12","doi-asserted-by":"publisher","first-page":"75ra26","DOI":"10.1126\/scitranslmed.3002003","volume":"3","author":"LV Sequist","year":"2011","unstructured":"Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3, 75ra26 (2011).","journal-title":"Sci. Transl. Med."},{"key":"49360_CR13","first-page":"100007","volume":"1","author":"N Roper","year":"2020","unstructured":"Roper, N. et al. Clonal evolution and heterogeneity of osimertinib acquired resistance mechanisms in EGFR mutant lung cancer. Lung Cancer Cell Rep. Med. 1, 100007 (2020).","journal-title":"Lung Cancer Cell Rep. Med."},{"key":"49360_CR14","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1158\/2159-8290.CD-16-0596","volume":"6","author":"JF Gainor","year":"2016","unstructured":"Gainor, J. F. et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov. 6, 1118\u20131133 (2016).","journal-title":"Cancer Discov."},{"key":"49360_CR15","doi-asserted-by":"publisher","first-page":"2382","DOI":"10.1056\/NEJMoa2105281","volume":"384","author":"MM Awad","year":"2021","unstructured":"Awad, M. M. et al. Acquired resistance to KRAS(G12C) inhibition in cancer. N. Engl. J. Med. 384, 2382\u20132393 (2021).","journal-title":"N. Engl. J. Med."},{"key":"49360_CR16","doi-asserted-by":"publisher","first-page":"1643","DOI":"10.1016\/S1470-2045(16)30508-3","volume":"17","author":"G Goss","year":"2016","unstructured":"Goss, G. et al. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 17, 1643\u20131652 (2016).","journal-title":"Lancet Oncol."},{"key":"49360_CR17","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1056\/NEJMoa1913662","volume":"382","author":"SS Ramalingam","year":"2020","unstructured":"Ramalingam, S. S. et al. Overall survival with Osimertinib in untreated, EGFR-mutated advanced NSCLC. N. Engl. J. Med. 382, 41\u201350 (2020).","journal-title":"N. Engl. J. Med."},{"key":"49360_CR18","doi-asserted-by":"publisher","first-page":"2613","DOI":"10.3390\/cancers14112613","volume":"14","author":"C Delahaye","year":"2022","unstructured":"Delahaye, C. et al.Early steps of resistance to targeted therapies in non-small-cell lung cancer. Cancers 14, 2613 (2022).","journal-title":"Cancers"},{"key":"49360_CR19","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1038\/nm.4040","volume":"22","author":"AN Hata","year":"2016","unstructured":"Hata, A. N. et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat. Med. 22, 262\u2013269 (2016).","journal-title":"Nat. Med."},{"key":"49360_CR20","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.cell.2010.02.027","volume":"141","author":"SV Sharma","year":"2010","unstructured":"Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69\u201380 (2010).","journal-title":"Cell"},{"key":"49360_CR21","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10690","volume":"7","author":"M Ramirez","year":"2016","unstructured":"Ramirez, M. et al. Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells. Nat. Commun. 7, 10690 (2016).","journal-title":"Nat. Commun."},{"key":"49360_CR22","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.ccell.2019.12.006","volume":"37","author":"KJ Kurppa","year":"2020","unstructured":"Kurppa, K. J. et al. Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway. Cancer Cell 37, 104\u2013122 e112 (2020).","journal-title":"Cancer Cell"},{"key":"49360_CR23","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/j.jtho.2022.12.003","volume":"18","author":"N Moghal","year":"2023","unstructured":"Moghal, N. et al. Single-cell analysis reveals transcriptomic features of drug-tolerant persisters and stromal adaptation in a patient-derived EGFR-mutated lung adenocarcinoma xenograft model. J. Thorac. Oncol. 18, 499\u2013515 (2023).","journal-title":"J. Thorac. Oncol."},{"key":"49360_CR24","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1038\/nature24297","volume":"551","author":"MJ Hangauer","year":"2017","unstructured":"Hangauer, M. J. et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551, 247\u2013250 (2017).","journal-title":"Nature"},{"key":"49360_CR25","doi-asserted-by":"publisher","first-page":"2666","DOI":"10.1158\/2159-8290.CD-22-0111","volume":"12","author":"A Noronha","year":"2022","unstructured":"Noronha, A. et al. AXL and Error-Prone DNA replication confer drug resistance and offer strategies to treat EGFR-mutant lung cancer. Cancer Discov. 12, 2666\u20132683 (2022).","journal-title":"Cancer Discov."},{"key":"49360_CR26","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1038\/s41586-023-06342-8","volume":"620","author":"Y Goyal","year":"2023","unstructured":"Goyal, Y. et al. Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells. Nature 620, 651\u2013659 (2023).","journal-title":"Nature"},{"key":"49360_CR27","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/j.ccell.2017.07.002","volume":"32","author":"GD Guler","year":"2017","unstructured":"Guler, G. D. et al. Repression of stress-induced LINE-1 expression protects cancer cell subpopulations from lethal drug exposure.Cancer Cell 32, 221\u2013237 e213 (2017).","journal-title":"Cancer Cell"},{"key":"49360_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21884-z","volume":"12","author":"AF Aissa","year":"2021","unstructured":"Aissa, A. F. et al. Single-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer. Nat. Commun. 12, 1628 (2021).","journal-title":"Nat. Commun."},{"key":"49360_CR29","doi-asserted-by":"crossref","unstructured":"Pu, Y. et al. Drug-tolerant persister cells in cancer: the cutting edges and future directions. Nat Rev. Clin. Oncol. 20, (2023).","DOI":"10.1038\/s41571-023-00815-5"},{"key":"49360_CR30","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/j.cell.2018.06.025","volume":"174","author":"F Rambow","year":"2018","unstructured":"Rambow, F. et al. Toward minimal residual disease-directed therapy in melanoma. Cell 174, 843\u2013855 e819 (2018).","journal-title":"Cell"},{"key":"49360_CR31","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-02085-1","volume":"21","author":"CE Eyler","year":"2020","unstructured":"Eyler, C. E. et al. Single-cell lineage analysis reveals genetic and epigenetic interplay in glioblastoma drug resistance. Genome Biol. 21, 174 (2020).","journal-title":"Genome Biol."},{"key":"49360_CR32","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/j.cell.2020.11.018","volume":"184","author":"SK Rehman","year":"2021","unstructured":"Rehman, S. K. et al. Colorectal cancer cells enter a diapause-like DTP state to survive chemotherapy. Cell 184, 226\u2013242 e221 (2021).","journal-title":"Cell"},{"key":"49360_CR33","doi-asserted-by":"crossref","unstructured":"Echeverria, G. V. Resistance to\u00ffneoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state. Sci. Transl. Med. (2019).","DOI":"10.1126\/scitranslmed.aav0936"},{"key":"49360_CR34","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1038\/nature13611","volume":"514","author":"A Viale","year":"2014","unstructured":"Viale, A. et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628\u2013632 (2014).","journal-title":"Nature"},{"key":"49360_CR35","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1038\/s41586-021-03796-6","volume":"596","author":"Y Oren","year":"2021","unstructured":"Oren, Y. et al. Cycling cancer persister cells arise from lineages with distinct programs. Nature 596, 576\u2013582 (2021).","journal-title":"Nature"},{"key":"49360_CR36","doi-asserted-by":"publisher","first-page":"3356","DOI":"10.1016\/j.cell.2022.07.025","volume":"185","author":"H Kalkavan","year":"2022","unstructured":"Kalkavan, H. et al. Sublethal cytochrome c release generates drug-tolerant persister cells. Cell 185, 3356\u20133374 e3322 (2022).","journal-title":"Cell"},{"key":"49360_CR37","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/nchembio.2085","volume":"12","author":"M Vinogradova","year":"2016","unstructured":"Vinogradova, M. et al. An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells. Nat. Chem. Biol. 12, 531\u2013538 (2016).","journal-title":"Nat. Chem. Biol."},{"key":"49360_CR38","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1158\/2159-8290.CD-17-0461","volume":"8","author":"M Rusan","year":"2018","unstructured":"Rusan, M. et al. Suppression of adaptive responses to targeted cancer therapy by transcriptional repression. Cancer Discov. 8, 59\u201373 (2018).","journal-title":"Cancer Discov."},{"key":"49360_CR39","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1038\/s41591-018-0264-7","volume":"25","author":"KN Shah","year":"2019","unstructured":"Shah, K. N. et al. Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer. Nat. Med. 25, 111\u2013118 (2019).","journal-title":"Nat. Med."},{"key":"49360_CR40","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1016\/j.ccell.2021.07.006","volume":"39","author":"K Tanaka","year":"2021","unstructured":"Tanaka, K. et al. Targeting aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis. Cancer Cell 39, 1245\u20131261 e1246 (2021).","journal-title":"Cancer Cell"},{"key":"49360_CR41","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-08074-0","volume":"10","author":"H Taniguchi","year":"2019","unstructured":"Taniguchi, H. et al. AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells. Nat. Commun. 10, 259 (2019).","journal-title":"Nat. Commun."},{"key":"49360_CR42","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.bcp.2018.11.004","volume":"162","author":"FM Vallette","year":"2019","unstructured":"Vallette, F. M. et al. Dormant, quiescent, tolerant and persister cells: Four synonyms for the same target in cancer. Biochem. Pharm. 162, 169\u2013176 (2019).","journal-title":"Biochem. Pharm."},{"key":"49360_CR43","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/j.cell.2007.12.033","volume":"132","author":"A Sakaue-Sawano","year":"2008","unstructured":"Sakaue-Sawano, A. et al. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell 132, 487\u2013498 (2008).","journal-title":"Cell"},{"key":"49360_CR44","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.ccr.2009.11.022","volume":"17","author":"AB Turke","year":"2010","unstructured":"Turke, A. B. et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17, 77\u201388 (2010).","journal-title":"Cancer Cell"},{"key":"49360_CR45","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1038\/s41586-020-2922-4","volume":"587","author":"KJ Travaglini","year":"2020","unstructured":"Travaglini, K. J. et al. A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature 587, 619\u2013625 (2020).","journal-title":"Nature"},{"key":"49360_CR46","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-022-00337-w","volume":"6","author":"SW Criscione","year":"2022","unstructured":"Criscione, S. W. et al. The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells. NPJ Precis Oncol. 6, 95 (2022).","journal-title":"NPJ Precis Oncol."},{"key":"49360_CR47","doi-asserted-by":"publisher","first-page":"2721466","DOI":"10.1155\/2021\/2721466","volume":"2021","author":"Y Liu","year":"2021","unstructured":"Liu, Y. et al. Enhancing the therapeutic efficacy of KRAS(G12C) inhibitors in lung adenocarcinoma cell models by cotargeting the MAPK pathway or HSP90. J. Oncol. 2021, 2721466 (2021).","journal-title":"J. Oncol."},{"key":"49360_CR48","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-021-00250-8","volume":"6","author":"K Tanimura","year":"2022","unstructured":"Tanimura, K. et al. HER3 activation contributes toward the emergence of ALK inhibitor-tolerant cells in ALK-rearranged lung cancer with mesenchymal features. NPJ Precis Oncol. 6, 5 (2022).","journal-title":"NPJ Precis Oncol."},{"key":"49360_CR49","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1038\/ng.3218","volume":"47","author":"L Lin","year":"2015","unstructured":"Lin, L. et al. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat. Genet. 47, 250\u2013256 (2015).","journal-title":"Nat. Genet."},{"key":"49360_CR50","doi-asserted-by":"publisher","first-page":"3427","DOI":"10.1242\/jcs.206433","volume":"130","author":"K Rottner","year":"2017","unstructured":"Rottner, K., Faix, J., Bogdan, S., Linder, S. & Kerkhoff, E. Actin assembly mechanisms at a glance. J. Cell Sci. 130, 3427\u20133435 (2017).","journal-title":"J. Cell Sci."},{"key":"49360_CR51","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1242\/jcs.064964","volume":"124","author":"ST Sit","year":"2011","unstructured":"Sit, S. T. & Manser, E. Rho GTPases and their role in organizing the actin cytoskeleton. J. Cell Sci. 124, 679\u2013683 (2011).","journal-title":"J. Cell Sci."},{"key":"49360_CR52","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1038\/nrm.2016.67","volume":"17","author":"RG Hodge","year":"2016","unstructured":"Hodge, R. G. & Ridley, A. J. Regulating rho GTPases and their regulators. Nat. Rev. Mol. Cell Biol. 17, 496\u2013510 (2016).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"49360_CR53","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1038\/s41557-019-0237-6","volume":"11","author":"EM Storck","year":"2019","unstructured":"Storck, E. M. et al. Dual chemical probes enable quantitative system-wide analysis of protein prenylation and prenylation dynamics. Nat. Chem. 11, 552\u2013561 (2019).","journal-title":"Nat. Chem."},{"key":"49360_CR54","doi-asserted-by":"publisher","first-page":"1856","DOI":"10.1200\/JCO.20.02903","volume":"39","author":"AL Ho","year":"2021","unstructured":"Ho, A. L. et al. Tipifarnib in head and neck squamous cell carcinoma with HRAS mutations. J. Clin. Oncol. 39, 1856\u20131864 (2021).","journal-title":"J. Clin. Oncol."},{"key":"49360_CR55","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1016\/j.tcb.2018.02.006","volume":"28","author":"Z Shu","year":"2018","unstructured":"Shu, Z., Row, S. & Deng, W. M. Endoreplication: the good, the bad, and the ugly. Trends Cell Biol. 28, 465\u2013474 (2018).","journal-title":"Trends Cell Biol."},{"key":"49360_CR56","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/s41418-017-0040-0","volume":"25","author":"A Gandarillas","year":"2018","unstructured":"Gandarillas, A., Molinuevo, R. & Sanz-Gomez, N. Mammalian endoreplication emerges to reveal a potential developmental timer. Cell Death Differ. 25, 471\u2013476 (2018).","journal-title":"Cell Death Differ."},{"key":"49360_CR57","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1016\/j.jtho.2018.12.021","volume":"14","author":"A Quintanal-Villalonga","year":"2019","unstructured":"Quintanal-Villalonga, A. et al. FGFR1 cooperates with egfr in lung cancer oncogenesis, and their combined inhibition shows improved efficacy. J. Thorac. Oncol. 14, 641\u2013655 (2019).","journal-title":"J. Thorac. Oncol."},{"key":"49360_CR58","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1002\/ijc.30047","volume":"139","author":"M Yang","year":"2016","unstructured":"Yang, M. et al. NSCLC harboring EGFR exon-20 insertions after the regulatory C-helix of kinase domain responds poorly to known EGFR inhibitors. Int J. Cancer 139, 171\u2013176 (2016).","journal-title":"Int J. Cancer"},{"key":"49360_CR59","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1186\/s13046-018-0871-7","volume":"37","author":"I Ferrer","year":"2018","unstructured":"Ferrer, I. et al. MAP17 predicts sensitivity to platinum-based therapy, EGFR inhibitors and the proteasome inhibitor bortezomib in lung adenocarcinoma. J. Exp. Clin. Cancer Res. 37, 195 (2018).","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"49360_CR60","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. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497\u20131500 (2004).","journal-title":"Science"},{"key":"49360_CR61","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":"49360_CR62","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1016\/j.cell.2020.07.017","volume":"182","author":"A Maynard","year":"2020","unstructured":"Maynard, A. et al. Therapy-induced evolution of human lung cancer revealed by single-cell RNA sequencing. Cell 182, 1232\u20131251 e1222 (2020).","journal-title":"Cell"},{"key":"49360_CR63","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1158\/2159-8290.CD-23-0289","volume":"14","author":"Z Li","year":"2024","unstructured":"Li, Z. et al. Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma. Cancer Discov. 14, 308\u2013325 (2024).","journal-title":"Cancer Discov."},{"key":"49360_CR64","doi-asserted-by":"publisher","first-page":"1478","DOI":"10.1016\/j.cell.2023.02.010","volume":"186","author":"K Shiraishi","year":"2023","unstructured":"Shiraishi, K. et al. Biophysical forces mediated by respiration maintain lung alveolar epithelial cell fate. Cell 186, 1478\u20131492 e1415 (2023).","journal-title":"Cell"},{"key":"49360_CR65","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.ccell.2019.12.003","volume":"37","author":"JL Orgaz","year":"2020","unstructured":"Orgaz, J. L. et al. Myosin II reactivation and cytoskeletal remodeling as a hallmark and a vulnerability in melanoma therapy resistance. Cancer Cell 37, 85\u2013103 e109 (2020).","journal-title":"Cancer Cell"},{"key":"49360_CR66","doi-asserted-by":"publisher","first-page":"4219","DOI":"10.1128\/MCB.23.12.4219-4229.2003","volume":"23","author":"K Riento","year":"2003","unstructured":"Riento, K., Guasch, R. M., Garg, R., Jin, B. & Ridley, A. J. RhoE binds to ROCK I and inhibits downstream signaling. Mol. Cell Biol. 23, 4219\u20134229 (2003).","journal-title":"Mol. Cell Biol."},{"key":"49360_CR67","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1002\/cphy.c150018","volume":"6","author":"W Jie","year":"2015","unstructured":"Jie, W. et al. Pathophysiological functions of Rnd3\/RhoE. Compr. Physiol. 6, 169\u2013186 (2015).","journal-title":"Compr. Physiol."},{"key":"49360_CR68","doi-asserted-by":"publisher","first-page":"30451","DOI":"10.1074\/jbc.M003469200","volume":"275","author":"HR Ashar","year":"2000","unstructured":"Ashar, H. R. et al. Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules. J. Biol. Chem. 275, 30451\u201330457 (2000).","journal-title":"J. Biol. Chem."},{"key":"49360_CR69","doi-asserted-by":"publisher","first-page":"3403","DOI":"10.1242\/jcs.115.17.3403","volume":"115","author":"D Hussein","year":"2002","unstructured":"Hussein, D. & Taylor, S. S. Farnesylation of Cenp-F is required for G2\/M progression and degradation after mitosis. J. cell Sci. 115, 3403\u20133414 (2002).","journal-title":"J. cell Sci."},{"key":"49360_CR70","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1083\/jcb.151.6.1155","volume":"151","author":"RD Moir","year":"2000","unstructured":"Moir, R. D., Yoon, M., Khuon, S. & Goldman, R. D. Nuclear lamins A and B1: different pathways of assembly during nuclear envelope formation in living cells. J. Cell Biol. 151, 1155\u20131168 (2000).","journal-title":"J. Cell Biol."},{"key":"49360_CR71","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1016\/j.cell.2017.04.022","volume":"169","author":"B van Steensel","year":"2017","unstructured":"van Steensel, B. & Belmont, A. S. Lamina-associated domains: links with chromosome architecture, heterochromatin, and gene repression. Cell 169, 780\u2013791 (2017).","journal-title":"Cell"},{"key":"49360_CR72","doi-asserted-by":"crossref","unstructured":"Costa-Mattioli, M. & Walter, P. The integrated stress response: From mechanism to disease. Science 386, (2020).","DOI":"10.1126\/science.aat5314"},{"key":"49360_CR73","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.15252\/embr.201642195","volume":"17","author":"K Pakos-Zebrucka","year":"2016","unstructured":"Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374\u20131395 (2016).","journal-title":"EMBO Rep."},{"key":"49360_CR74","doi-asserted-by":"publisher","first-page":"ra17","DOI":"10.1126\/scisignal.aac4380","volume":"9","author":"J Ishizawa","year":"2016","unstructured":"Ishizawa, J. et al. ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. Sci. Signal 9, ra17 (2016).","journal-title":"Sci. Signal"},{"key":"49360_CR75","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1007\/s10637-018-0662-1","volume":"37","author":"K Jazieh","year":"2019","unstructured":"Jazieh, K. et al. A phase I study of the farnesyltransferase inhibitor Tipifarnib in combination with the epidermal growth factor tyrosine kinase inhibitor Erlotinib in patients with advanced solid tumors. Invest N. Drugs 37, 307\u2013314 (2019).","journal-title":"Invest N. Drugs"},{"key":"49360_CR76","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.1038\/s41587-020-0591-3","volume":"38","author":"V Bergen","year":"2020","unstructured":"Bergen, V., Lange, M., Peidli, S., Wolf, F. A. & Theis, F. J. Generalizing RNA velocity to transient cell states through dynamical modeling. Nat. Biotechnol. 38, 1408\u20131414 (2020).","journal-title":"Nat. Biotechnol."},{"key":"49360_CR77","doi-asserted-by":"publisher","first-page":"e133","DOI":"10.1093\/nar\/gkz601","volume":"47","author":"F Pont","year":"2019","unstructured":"Pont, F., Tosolini, M. & Fournie, J. J. Single-cell signature explorer for comprehensive visualization of single cell signatures across scRNA-seq datasets. Nucleic Acids Res. 47, e133 (2019).","journal-title":"Nucleic Acids Res."},{"key":"49360_CR78","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-023-05150-1","volume":"24","author":"F Pont","year":"2023","unstructured":"Pont, F. et al. Single-cell spatial explorer: easy exploration of spatial and multimodal transcriptomics. BMC Bioinformatics. 24, 30 (2023).","journal-title":"BMC Bioinformatics."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-49360-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-49360-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-49360-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T06:04:20Z","timestamp":1719468260000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-49360-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,27]]},"references-count":78,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["49360"],"URL":"https:\/\/doi.org\/10.1038\/s41467-024-49360-4","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,27]]},"assertion":[{"value":"2 March 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 June 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 June 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"O.C. reports research funding from Kura Oncology through a sponsored research contract. L.K. reports personal fees from Kura Oncology during the conduct of the study and personal fees from Kura Oncology outside the submitted work. FB is an employee and stockholder of Kura Oncology. JM reports personal fees\/advisory board membership from Roche and Bristol Myers Squibb, and AstraZeneca, advisory board membership and research funding (institution), personal fees\/advisory board membership from Pfizer, Novartis, Amgen, Takeda, Daiichi Sankyo, the healthcare business of Merck KGaA, Darmstadt, Germany, grants\/funding (institution) from Roche\/Genentech, Bristol Myers Squibb, Pierre Fabre and AstraZeneca outside the submitted work. L.P.A has leadership interest (board member) in ALTUM Sequencing and Genomica; has received honoraria for participation at meetings from Amgen Sanofi, AstraZeneca Spain, Bayer, Blueprint Medicines, Bristol Myers Squibb\/Celgene, Daiichi Sankyo, Ipsen, Lilly, Merck Serono, Mirati Therapeutics, Novartis, Pfizer, PharmaMar, Roche\/Genentech, Servier, and Takeda; speakers\u2019 bureau from AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD Oncology, Pfizer, and Roche\/Genentech; research funding (via his institution) from AstraZeneca, Bristol Myers Squibb, Kura Oncology, MSD, Pfizer and PharmaMar; and travel and accommodation expenses from AstraZeneca, Bristol Myers Squibb\/Celgene, MSD, Pfizer Roche\/Genentech, and Takeda. L.P-A. also declares other relationships with Amgen, Ipsen, Merck, Novartis, Pfizer, Roche, Sanofi, and Servier (as sponsors of clinical trials), outside the submitted work. The remaining authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5345"}}