{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T17:50:36Z","timestamp":1791481836328,"version":"4.3.4"},"posted":{"date-parts":[[2026,10,4]]},"group-title":"Cancer Biology","reference-count":76,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Metabolic plasticity contributes to therapeutic resistance in T-cell lymphoma, but the metabolic dependencies underlying tyrosine kinase inhibitor (TKI) resistance remain poorly understood. ATP citrate lyase (ACLY), which converts citrate to cytosolic acetyl-CoA, links glucose metabolism to lipogenesis and acetylation-dependent regulation. We hypothesized that ACLY represents an actionable metabolic vulnerability in lymphoma.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Structure-guided drug discovery and biochemical screening were used to identify the novel ACLY inhibitor VCB1. VCB1 was evaluated against recombinant human ACLY and in TKI-sensitive and TKI-resistant lymphoma models. Antitumor activity was assessed by proliferation, cell-cycle analysis, apoptosis, and immunoblotting, followed by integrated transcriptomic, metabolomic, and lipidomic profiling.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Our xenograft study showed that ACLY dependence in ALK+ALCL. We discovered novel ACLY inhibitor VCB1 directly inhibited recombinant ACLY with \u00b5M potency (IC\u2085\u2080, 0.9 \u00b5M) and strongly suppressed lymphoma cell growth. In ALK inhibitor-sensitive SUPM2, VCB1 showed an IC\u2085\u2080 of 0.299 \u03bcM and retained potency in lorlatinib-resistant SUPM2-LR1000 cells (1.62 \u03bcM), whereas BMS-303141 was substantially less active (17.46 and 22.07 \u03bcM). VCB1 similarly inhibited BTK inhibitor sensitive and resistant mantle cell lymphoma cell growth (IC\u2085\u2080, 0.28 and 0.278 \u03bcM), compared with BMS-303141 (30.5 and 37.01 \u03bcM). Multi-omics profiling revealed suppression of de novo lipogenesis, including\n                    <jats:italic>ACACA, FASN<\/jats:italic>\n                    , and\n                    <jats:italic>PPARGC1B<\/jats:italic>\n                    , together with extensive remodeling of triglyceride, phospholipid, cardiolipin, ceramide, and acylcarnitine species and increased expression of fatty-acid oxidation genes. VCB1 activated the integrated stress response (ISR), inducing\n                    <jats:italic>ATF4, PPP1R15A, DDIT3, DDIT4<\/jats:italic>\n                    and\n                    <jats:italic>SESN2<\/jats:italic>\n                    , while disrupting purine and pyrimidine metabolism and reducing nucleotide biosynthetic genes, including\n                    <jats:italic>CAD, DHODH, UCK2<\/jats:italic>\n                    , and\n                    <jats:italic>ATIC<\/jats:italic>\n                    . VCB1 further activated an ACLY\u2013ISR\u2013CHAC1 axis associated with reduced GCLC\/GCLM expression, glutathione depletion, and a decreased GSH\/GSSG ratio, indicating impaired redox homeostasis. TKI-resistant cells exhibited distinct lipid-metabolic remodeling consistent with metabolic plasticity. VCB1 also altered immune-regulatory programs involving\n                    <jats:italic>PDCD1, TIGIT, CD247, CD226, NFATC2<\/jats:italic>\n                    , and inflammatory cytokines. Functionally, VCB1 induced cell cycle arrest and apoptosis.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>ACLY represents an integrated metabolic and signaling vulnerability in lymphoma. VCB1 suppresses lymphoma growth across TKI-sensitive and resistant models by disrupting lipid and nucleotide metabolism, metabolic adaptation and ISR and redox homeostasis supporting ACLY inhibition as a therapeutic strategy for TKI-resistant lymphoma.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.29.755331","type":"posted-content","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T16:25:11Z","timestamp":1791131111000},"source":"Crossref","is-referenced-by-count":0,"title":["A Novel ACLY Inhibitor Induces Transcriptional and Metabolic Reprogramming to Overcome Tyrosine kinase inhibitor Resistance in Lymphoma"],"prefix":"10.64898","author":[{"given":"Nagarajan","family":"Pattabiraman","sequence":"first","affiliation":[{"name":"Veracure Biosciences Inc., Gaithersburg, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cosimo","family":"Lobello","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Rushmore","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengchun","family":"Wang","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Mologni","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hossein","family":"Borghaei","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavindra","family":"Nath","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wujuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Proteomics & Metabolomics Shared Resource, The Wistar Institute, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron R.","family":"Goldman","sequence":"additional","affiliation":[{"name":"Proteomics & Metabolomics Shared Resource, The Wistar Institute, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Nejati","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariusz","family":"Wasik","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnvesly","family":"Basappa","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100810001974000_2026.09.29.755331v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1164097"},{"key":"2026100810001974000_2026.09.29.755331v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2019.12.010"},{"key":"2026100810001974000_2026.09.29.755331v1.3","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2012-3709"},{"issue":"5","key":"2026100810001974000_2026.09.29.755331v1.4","first-page":"1169","article-title":"Phosphorylation of recombinant human ATP : citrate lyase by cAMP-dependent protein kinase abolishes homotropic allosteric regulation of the enzyme by citrate and increases the enzyme activity","volume":"39","year":"2000","journal-title":"Allosteric activation of ATP : citrate lyase by phosphorylated sugars. 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