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Of these, we confirmed that inhibitors of the lysine-specific demethylase (LSD1; also known as KDM1A) rewired kinase signaling in AML cells in a way that increased the activity of the kinase MEK and that broadly suppressed the activity of other kinases and feedback loops. As a result, AML cell lines and about half of primary human AML samples were primed for sensitivity to the MEK inhibitor trametinib. Primary human cells with\n            <jats:italic>KRAS<\/jats:italic>\n            mutations and those with high MEK pathway activity were the best responders to sequential treatment with LSD1 inhibitors then trametinib, whereas those with\n            <jats:italic>NRAS<\/jats:italic>\n            mutations and high mTOR activity were poor responders. Overall, our study reveals the MEK pathway as a mechanism of resistance to LSD1 inhibitors in AML and shows a way to modulate kinase network circuitry to potentially overcome therapeutic resistance to kinase inhibitors.\n          <\/jats:p>","DOI":"10.1126\/scisignal.abl7989","type":"journal-article","created":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T17:54:21Z","timestamp":1650390861000},"source":"Crossref","is-referenced-by-count":17,"title":["Targeting the lysine-specific demethylase 1 rewires kinase networks and primes leukemia cells for kinase inhibitor treatment"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7281-8296","authenticated-orcid":true,"given":"Federico","family":"Pedicona","sequence":"first","affiliation":[{"name":"Cell Signaling and Proteomics Group, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4207-9349","authenticated-orcid":true,"given":"Pedro","family":"Casado","sequence":"additional","affiliation":[{"name":"Cell Signaling and Proteomics Group, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0861-7577","authenticated-orcid":true,"given":"Maruan","family":"Hijazi","sequence":"additional","affiliation":[{"name":"Cell Signaling and Proteomics Group, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8505-7430","authenticated-orcid":true,"given":"John G.","family":"Gribben","sequence":"additional","affiliation":[{"name":"Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7671-7364","authenticated-orcid":true,"given":"Kevin","family":"Rouault-Pierre","sequence":"additional","affiliation":[{"name":"Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3426-2274","authenticated-orcid":true,"given":"Pedro R.","family":"Cutillas","sequence":"additional","affiliation":[{"name":"Cell Signaling and Proteomics Group, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK."},{"name":"Alan Turing Institute, British Library, 2QR, 96 Euston Road, London NW1 2DB, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0782-4"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1073096"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1103782"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10662"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)00106-6"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.36.1196"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1614359"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.28.9678"},{"key":"e_1_3_3_11_2","first-page":"3065","article-title":"Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer","volume":"118","author":"Carracedo A.","year":"2008","unstructured":"A. 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