{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:16Z","timestamp":1792790356346,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,24]]},"group-title":"Cancer Biology","reference-count":52,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Intramural Research Program of the National Institutes of Health"},{"name":"Ludwig Center at Harvard University","id":[{"id":"https:\/\/ror.org\/03vek6s52","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Cancer Institute F99\/K00 Pre-Postdoctoral Transition Fellowship"},{"name":"Emerald Foundation\/Black in Cancer Career Transition Award","id":[{"id":"https:\/\/ror.org\/031tb8x29","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Cancer Institute R35 Award"},{"id":[{"id":"https:\/\/ror.org\/0348ff195","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/027xav248","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Resistance to CDK4\/6 inhibitors limits the durability of therapy for ER+ breast cancer. Despite the identification of mechanisms that regulate resistance, the metabolic adaptations that enable therapeutic escape remain poorly understood. Here, we identify a metabolic\u2013epigenetic circuit that drives resistance by coordinately rewiring amino acid and glucose metabolism. CDK4\/6 inhibitor\u2013resistant ER+ tumor cells upregulate the leucine transporter SLC7A5, enhancing leucine uptake. SLC7A5 overexpression is sufficient to confer palbociclib resistance across ER+ cell lines, patient-derived organoids and xenografts. Stable isotope tracing in cell lines and in xenograft tumors revealed that leucine is catabolized through BCAT2 and HMGCL to increase acetyl-CoA levels, and elevated acetyl-CoA promotes H3K27 acetylation at the GLUT1 promoter, upregulating GLUT1 expression and glycolytic activity. Disrupting leucine transport, catabolism, or availability suppresses GLUT1 expression and restores therapeutic sensitivity in resistant models. In patients receiving palbociclib-based therapy, high SLC7A5 expression and coordinated SLC7A5\u2013GLUT1 co-expression are associated with shorter progression-free survival. Together, these findings define a metabolic\u2013 epigenetic mechanism linking branched-chain amino acid catabolism to glycolysis and identify a biomarker-associated metabolic vulnerability in advanced ER+ breast cancer.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of Significance<\/jats:title>\n                  <jats:p>Resistance to CDK4\/6 inhibitors is nearly universal in ER+ breast cancer. We identify a metabolic\u2013 epigenetic circuit in which acetyl-coA derived from leucine catabolism promotes epigenetic changes at the GLUT1 promoter, thereby increasing glucose uptake and driving glycolysis. Disrupting leucine transport, catabolism, or availability suppresses this program and restores drug sensitivity, identifying crosstalk between amino acid metabolism and glycolysis in regulating drug resistance. High expression of the leucine transporter, SLC7A5, is associated with shorter progression-free survival, revealing a biomarker-associated metabolic vulnerability.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.23.752387","type":"posted-content","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T11:25:13Z","timestamp":1790249113000},"source":"Crossref","is-referenced-by-count":0,"title":["Metabolic\u2013epigenetic coupling between leucine catabolism and glycolysis drives CDK4\/6 inhibitor resistance"],"prefix":"10.64898","author":[{"given":"Michael UJ","family":"Oliphant","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Cancer Research Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klarisa","family":"Norton","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiran","family":"Kurmi","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard","family":"Yang","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shakchhi","family":"Joshi","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonah","family":"Lee","sequence":"additional","affiliation":[{"name":"Cancer Research Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"},{"name":"Preclinical Murine Pharmacogenetics Facility and Mouse Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Kozlova","sequence":"additional","affiliation":[{"name":"Cancer Research Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taru","family":"Muranen","sequence":"additional","affiliation":[{"name":"Cancer Research Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G","family":"Clohessy","sequence":"additional","affiliation":[{"name":"Cancer Research Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"},{"name":"Preclinical Murine Pharmacogenetics Facility and Mouse Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcia","family":"Haigis","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Senthil K","family":"Muthuswamy","sequence":"additional","affiliation":[{"name":"Cancer Research Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"},{"name":"Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092807404832000_2026.09.23.752387v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.12.006"},{"key":"2026092807404832000_2026.09.23.752387v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"2026092807404832000_2026.09.23.752387v1.3","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-3009"},{"key":"2026092807404832000_2026.09.23.752387v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00378-6"},{"key":"2026092807404832000_2026.09.23.752387v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3504"},{"key":"2026092807404832000_2026.09.23.752387v1.6","first-page":"418833","article-title":"The influence of metabolism on drug response in cancer","volume":"8","year":"2018","journal-title":"Front. Oncol"},{"key":"2026092807404832000_2026.09.23.752387v1.7","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.trecan.2021.02.004","article-title":"Metabolic Reprogramming in Anticancer Drug Resistance: A Focus on Amino Acids","volume":"7","year":"2021","journal-title":"Trends Cancer"},{"key":"2026092807404832000_2026.09.23.752387v1.8","doi-asserted-by":"crossref","unstructured":"Lv, L. et al. Relationship between metabolic reprogramming and drug resistance in breast cancer. Front. Oncol. 12, (2022).","DOI":"10.3389\/fonc.2022.942064"},{"key":"2026092807404832000_2026.09.23.752387v1.9","first-page":"141","article-title":"Targeting cancer metabolism in the era of precision oncology","volume":"21","year":"2021","journal-title":"Nature Reviews Drug Discovery"},{"key":"2026092807404832000_2026.09.23.752387v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2023.07.006"},{"key":"2026092807404832000_2026.09.23.752387v1.11","doi-asserted-by":"crossref","unstructured":"Lemberg, K. M. , Gori, S. S. , Tsukamoto, T. , Rais, R. & Slusher, B. S . Clinical development of metabolic inhibitors for oncology. J. Clin. Invest. 132, (2022).","DOI":"10.1172\/JCI148550"},{"key":"2026092807404832000_2026.09.23.752387v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.12.039"},{"key":"2026092807404832000_2026.09.23.752387v1.13","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21863"},{"key":"2026092807404832000_2026.09.23.752387v1.14","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-070909-182917"},{"key":"2026092807404832000_2026.09.23.752387v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1126-2"},{"key":"2026092807404832000_2026.09.23.752387v1.16","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-018-0946-6"},{"key":"2026092807404832000_2026.09.23.752387v1.17","doi-asserted-by":"crossref","unstructured":"Kanai, Y . Amino acid transporter LAT1 (SLC7A5) as a molecular target for cancer diagnosis and therapeutics. Pharmacol. Ther. 230, (2022).","DOI":"10.1016\/j.pharmthera.2021.107964"},{"key":"2026092807404832000_2026.09.23.752387v1.18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0233629"},{"key":"2026092807404832000_2026.09.23.752387v1.19","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-18-0317"},{"key":"2026092807404832000_2026.09.23.752387v1.20","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32020"},{"key":"2026092807404832000_2026.09.23.752387v1.21","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-1390"},{"key":"2026092807404832000_2026.09.23.752387v1.22","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/s43018-024-00893-z","article-title":"Resistance mechanisms and therapeutic strategies of CDK4 and CDK6 kinase targeting in cancer","volume":"6","year":"2025","journal-title":"Nature Cancer"},{"key":"2026092807404832000_2026.09.23.752387v1.23","first-page":"89","article-title":"The CDK4\/6 inhibitor revolution \u2014 a game-changing era for breast cancer treatment","volume":"21","year":"2023","journal-title":"Nature Reviews Clinical Oncology"},{"key":"2026092807404832000_2026.09.23.752387v1.24","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-3958"},{"key":"2026092807404832000_2026.09.23.752387v1.25","first-page":"1","article-title":"Exemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic\/transcriptomic determinants of resistance in a phase I\/II trial","volume":"15","year":"2024","journal-title":"Nature Communications"},{"key":"2026092807404832000_2026.09.23.752387v1.26","first-page":"1","article-title":"Comparative biomarker analysis of PALOMA-2\/3 trials for palbociclib","volume":"6","year":"2022","journal-title":"npj Precision Oncology"},{"key":"2026092807404832000_2026.09.23.752387v1.27","first-page":"1","article-title":"Co-expression effect of LLGL2 and SLC7A5 to predict prognosis in ER\u03b1-positive breast cancer","volume":"12","year":"2022","journal-title":"Scientific Reports"},{"key":"2026092807404832000_2026.09.23.752387v1.28","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-018-0741-3"},{"key":"2026092807404832000_2026.09.23.752387v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)53663-2"},{"key":"2026092807404832000_2026.09.23.752387v1.30","doi-asserted-by":"crossref","unstructured":"Sweatt, A. J. et al. Branched-chain amino acid catabolism: Unique segregation of pathway enzymes in organ systems and peripheral nerves. Am. J. Physiol. Endocrinol. Metab. 286, (2004).","DOI":"10.1152\/ajpendo.00276.2003"},{"key":"2026092807404832000_2026.09.23.752387v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6603(01)70017-7"},{"key":"2026092807404832000_2026.09.23.752387v1.32","doi-asserted-by":"crossref","first-page":"8059","DOI":"10.1007\/s00253-021-11612-4","article-title":"An overview of branched-chain amino acid aminotransferases: functional differences between mitochondrial and cytosolic isozymes in yeast and human","volume":"105","year":"2021","journal-title":"Appl. Microbiol. Biotechnol"},{"key":"2026092807404832000_2026.09.23.752387v1.33","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.chembiol.2025.01.002","article-title":"A genetically encoded fluorescent biosensor for visualization of acetyl-CoA in live cells","volume":"32","year":"2025","journal-title":"Cell Chem. Biol"},{"key":"2026092807404832000_2026.09.23.752387v1.34","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13073-023-01201-7","article-title":"Longitudinal multi-omics study of palbociclib resistance in HR-positive\/HER2-negative metastatic breast cancer","volume":"15","year":"2023","journal-title":"Genome Medicine"},{"key":"2026092807404832000_2026.09.23.752387v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2019.12.011"},{"key":"2026092807404832000_2026.09.23.752387v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-020-0375-3"},{"key":"2026092807404832000_2026.09.23.752387v1.37","doi-asserted-by":"publisher","DOI":"10.1126\/science.aab2674"},{"key":"2026092807404832000_2026.09.23.752387v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2020.04.002"},{"key":"2026092807404832000_2026.09.23.752387v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-020-0270-8"},{"key":"2026092807404832000_2026.09.23.752387v1.40","doi-asserted-by":"crossref","unstructured":"Xia, P. & Dubrovska, A . CD98 heavy chain as a prognostic biomarker and target for cancer treatment. Front. Oncol. 13, (2023).","DOI":"10.3389\/fonc.2023.1251100"},{"key":"2026092807404832000_2026.09.23.752387v1.41","doi-asserted-by":"crossref","unstructured":"Cappoli, N. , Jenkinson, M. D. , Dello Russo, C. & Dickens, D . LAT1, a novel pharmacological target for the treatment of glioblastoma. Biochem. Pharmacol. 201, (2022).","DOI":"10.1016\/j.bcp.2022.115103"},{"key":"2026092807404832000_2026.09.23.752387v1.42","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3390\/cancers14010229","article-title":"Contribution of LAT1-4F2hc in Urological Cancers via Toll-like Receptor and Other Vital Pathways","volume":"14","year":"2022","journal-title":"Cancers (Basel"},{"key":"2026092807404832000_2026.09.23.752387v1.43","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15006"},{"key":"2026092807404832000_2026.09.23.752387v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.01.038"},{"key":"2026092807404832000_2026.09.23.752387v1.45","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-0728"},{"key":"2026092807404832000_2026.09.23.752387v1.46","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-024-01896-5"},{"key":"2026092807404832000_2026.09.23.752387v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1126-2"},{"key":"2026092807404832000_2026.09.23.752387v1.48","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-0360"},{"key":"2026092807404832000_2026.09.23.752387v1.49","first-page":"232","article-title":"A human breast cancer-derived xenograft and organoid platform for drug discovery and precision oncology. Nat","volume":"3","year":"2022","journal-title":"Cancer"},{"key":"2026092807404832000_2026.09.23.752387v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.04.006"},{"key":"2026092807404832000_2026.09.23.752387v1.51","doi-asserted-by":"crossref","first-page":"101461","DOI":"10.1016\/j.xcrm.2024.101461","article-title":"PRMT1 promotes pancreatic cancer development and resistance to chemotherapy","volume":"5","year":"2024","journal-title":"Cell Rep. Med"},{"key":"2026092807404832000_2026.09.23.752387v1.52","unstructured":"Motulsky, H. Analyzing Data with GraphPad Prism. www.graphpad.com (1999)."}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.23.752387","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:40:57Z","timestamp":1790606457000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.09.23.752387"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,24]]},"references-count":52,"URL":"https:\/\/doi.org\/10.64898\/2026.09.23.752387","relation":{},"subject":[],"published":{"date-parts":[[2026,9,24]]},"subtype":"preprint"}}