{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T21:49:37Z","timestamp":1769636977928,"version":"3.49.0"},"reference-count":39,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01DE025184"],"award-info":[{"award-number":["U01DE025184"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30\u2010CA046592"],"award-info":[{"award-number":["P30\u2010CA046592"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["R01DE032699"],"award-info":[{"award-number":["R01DE032699"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["T32GM145470"],"award-info":[{"award-number":["T32GM145470"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["F31 CA206341\u201003"],"award-info":[{"award-number":["F31 CA206341\u201003"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DGE\u20101256260"],"award-info":[{"award-number":["DGE\u20101256260"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Head &amp; Neck"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Head and neck squamous cell carcinoma (HNSCC) is a malignancy with poor prognosis and survival. While epidermal growth factor receptor (EGFR) is a known driver of HNSCC, EGFR inhibitors show limited efficacy as monotherapies, suggesting that effective combination therapies are needed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed GeCKO and Kinase CRISPR library screens to identify candidate knockouts that increase EGFR inhibitor sensitivity in resistant HNSCC cells. We validated a candidate using the CellTiter\u2010Glo viability assay following RNA interference and investigated the mechanisms using apoptosis and cell cycle flow cytometry analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Kinase CRISPR library screens identified that\n                      <jats:italic>PIK3C2A<\/jats:italic>\n                      gene downregulation enhanced EGFR inhibitor sensitivity in resistant HNSCC cells. Viability assays further validated that\n                      <jats:italic>PIK3C2A<\/jats:italic>\n                      knockdown overcame EGFR inhibitor resistance in HNSCC cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our data suggests that\n                      <jats:italic>PIK3C2A<\/jats:italic>\n                      is a novel mediator of EGFR inhibitor resistance in HNSCC. Future studies are required to determine the mechanisms by which\n                      <jats:italic>PIK3C2A<\/jats:italic>\n                      drives EGFR inhibitor resistance.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hed.70048","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T07:55:34Z","timestamp":1758614134000},"page":"486-495","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>CRISPR<\/scp>\n                    Screens Identify\n                    <i>PIK3C2A<\/i>\n                    as a Novel Mediator of\n                    <scp>EGFR<\/scp>\n                    Inhibitor Resistance in Head and Neck Squamous Cell Carcinoma"],"prefix":"10.1002","volume":"48","author":[{"given":"Jiayu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of Michigan  Ann Arbor Michigan USA"},{"name":"Department of Otolaryngology\u2014Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan L.","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"},{"name":"Cellular and Molecular Biology Program University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aditi","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew C.","family":"Birkeland","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery University of California  Davis California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole L.","family":"Michmerhuizen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Michigan  Ann Arbor Michigan USA"},{"name":"Department of Otolaryngology\u2014Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Gensterblum\u2010Miller","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"},{"name":"Cellular and Molecular Biology Program University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingyi","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Michigan  Ann Arbor Michigan USA"},{"name":"Rogel Cancer Center University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Swiecicki","sequence":"additional","affiliation":[{"name":"Rogel Cancer Center University of Michigan  Ann Arbor Michigan USA"},{"name":"Department of Hematology Oncology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marisa","family":"Buchakjian","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8813-5537","authenticated-orcid":false,"given":"Molly","family":"Heft Neal","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven B.","family":"Chinn","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew E.","family":"Spector","sequence":"additional","affiliation":[{"name":"University of Pittsburgh Medical Center University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3238-1111","authenticated-orcid":false,"given":"J. Chad","family":"Brenner","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Michigan  Ann Arbor Michigan USA"},{"name":"Department of Otolaryngology\u2014Head and Neck Surgery University of Michigan  Ann Arbor Michigan USA"},{"name":"Cellular and Molecular Biology Program University of Michigan  Ann Arbor Michigan USA"},{"name":"Rogel Cancer Center University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-00224-3"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13020338"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1602252"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30066-3"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.68.1478"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31999-8"},{"issue":"15","key":"e_1_2_9_9_1","first-page":"3579","article-title":"Elevated Levels of Transforming Growth Factor \u03b1 and Epidermal Growth Factor Receptor Messenger RNA Are Early Markers of Carcinogenesis in Head and Neck Cancer","volume":"53","author":"Grandis J. 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