{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T23:39:57Z","timestamp":1770334797930,"version":"3.49.0"},"posted":{"date-parts":[[2026,1,23]]},"group-title":"Cancer Biology","reference-count":26,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P50 CA265826"],"award-info":[{"award-number":["P50 CA265826"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 CA137008"],"award-info":[{"award-number":["R01 CA137008"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 CA164273"],"award-info":[{"award-number":["R01 CA164273"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Targeting a Cure for Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Methylthioadenosine phosphorylase (MTAP) loss co-occurs with actionable genomic alterations in non-small cell lung cancer (NSCLC) and creates vulnerability to protein arginine methyltransferase 5 (PRMT5) inhibition. Estimates of prevalence of MTAP loss rely on next-generation sequencing which can underestimate copy losses. Moreover, the activity of PRMT5 inhibitors in oncogene-driven NSCLC is not well established.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We assessed MTAP expression by immunohistochemistry (IHC) in 243 NSCLCs (n=132 early stage, n=111 metastatic), including 33 specimens with paired lymph nodes. Antiproliferative activity of PRMT5 inhibitor monotherapy and in combination with tyrosine kinase inhibitors (TKIs) was evaluated in MTAP-deleted NSCLC cell lines harboring\n                    <jats:italic>EGFR<\/jats:italic>\n                    or\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutations or\n                    <jats:italic>ALK<\/jats:italic>\n                    rearrangements.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Among 243 NSCLC specimens from 240 patients (72% with driver alterations, 90% adenocarcinoma), MTAP loss was identified in 43 (18%) specimens from 40 (17%) patients, including 18 (14%) early-stage and 22 (20%) metastatic tumors. MTAP loss occurred in 24% of stage 4 driver-positive NSCLCs versus 14% of driver-negative tumors (p=0.314). Twenty (61%) lung-nodal pairs demonstrated concordance; eight cases only exhibited decreased MTAP expression in nodes. Variable sensitivity to PRMT5 inhibitors was observed in 22 MTAP-deleted NSCLC cell lines (9\n                    <jats:italic>EGFR<\/jats:italic>\n                    -mutant, 7\n                    <jats:italic>KRAS<\/jats:italic>\n                    -mutant, 6\n                    <jats:italic>ALK<\/jats:italic>\n                    -rearranged), with responses seen in TKI-sensitive and TKI-resistant lines. SDMA (symmetric dimethylarginine) expression did not predict PRMT5 inhibitor sensitivity. TKI + PRMT5 inhibitor combos had greater activity than monotherapy.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>MTAP loss occurs in 1-in-5 oncogene-driven metastatic NSCLCs. PRMT5 inhibitor activity is independent of TKI exposure, driver alteration, and SDMA expression and enhanced by addition of TKI. These findings support clinical evaluation of PRMT5 inhibitor + TKI combinations for advanced NSCLC.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.21.700721","type":"posted-content","created":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T04:55:13Z","timestamp":1769230513000},"source":"Crossref","is-referenced-by-count":0,"title":["Prevalence and Actionability of MTAP Loss in Oncogene-Driven Lung Cancer"],"prefix":"10.64898","author":[{"given":"Takashi","family":"Sakai","sequence":"first","affiliation":[{"name":"Mass General Brigham Cancer Institute and Department of Medicine, Massachusetts General Hospital"},{"name":"Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zofia","family":"Piotrowska","sequence":"additional","affiliation":[{"name":"Mass General Brigham Cancer Institute and Department of Medicine, Massachusetts General Hospital"},{"name":"Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte I.","family":"Wang","sequence":"additional","affiliation":[{"name":"Harvard Medical School"},{"name":"Center for Integrated Diagnostics, Massachusetts General Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6157-5489","authenticated-orcid":false,"given":"Beow Y.","family":"Yeap","sequence":"additional","affiliation":[{"name":"Mass General Brigham Cancer Institute and Department of Medicine, Massachusetts General Hospital"},{"name":"Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7397-2009","authenticated-orcid":false,"given":"Rebecca S.","family":"Heist","sequence":"additional","affiliation":[{"name":"Mass General Brigham Cancer Institute and Department of Medicine, Massachusetts General Hospital"},{"name":"Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica J.","family":"Lin","sequence":"additional","affiliation":[{"name":"Mass General Brigham Cancer Institute and Department of Medicine, Massachusetts General Hospital"},{"name":"Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren E.","family":"Highfield","sequence":"additional","affiliation":[{"name":"Mass General Brigham Cancer Institute and Department of Medicine, Massachusetts General Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer L.","family":"Petersen","sequence":"additional","affiliation":[{"name":"Mass General Brigham Cancer Institute and Department of Medicine, Massachusetts General Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mandeep","family":"Banwait","sequence":"additional","affiliation":[{"name":"Mass General Brigham Cancer Institute and Department of Medicine, Massachusetts General Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joyce","family":"Liang","sequence":"additional","affiliation":[{"name":"Mass General Brigham Cancer Institute and Department of Medicine, Massachusetts General Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manisha","family":"Madhavan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Massachusetts General Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6127-318X","authenticated-orcid":false,"given":"Aaron N.","family":"Hata","sequence":"additional","affiliation":[{"name":"Mass General Brigham Cancer Institute and Department of Medicine, Massachusetts General Hospital"},{"name":"Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9092-2265","authenticated-orcid":false,"given":"Mari","family":"Mino-Kenudson","sequence":"additional","affiliation":[{"name":"Harvard Medical School"},{"name":"Department of Pathology, Massachusetts General Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0781-9257","authenticated-orcid":false,"given":"Ibiayi","family":"Dagogo-Jack","sequence":"additional","affiliation":[{"name":"Mass General Brigham Cancer Institute and Department of Medicine, Massachusetts General Hospital"},{"name":"Harvard Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026020503012544000_2026.01.21.700721v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2025.104535"},{"key":"2026020503012544000_2026.01.21.700721v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.4971"},{"key":"2026020503012544000_2026.01.21.700721v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2025.08.014"},{"key":"2026020503012544000_2026.01.21.700721v1.4","doi-asserted-by":"crossref","unstructured":"Tonini MR . 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