{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T19:16:07Z","timestamp":1792264567671,"version":"4.4.0"},"reference-count":65,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"922","funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["NIDCR R01DE032501"],"award-info":[{"award-number":["NIDCR R01DE032501"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["RM1DE033491"],"award-info":[{"award-number":["RM1DE033491"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"NIDCR","doi-asserted-by":"crossref","award":["RM1DE033491"],"award-info":[{"award-number":["RM1DE033491"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2026,1,27]]},"abstract":"<jats:p>Pain associated with oral cancer is debilitating. Opioids are the gold standard for cancer pain management, but tolerance and side effects limit their use. Epidermal growth factor receptor (EGFR) signaling is commonly amplified in oral tumors. Here, we found that EGFR activation contributed to both oral cancer pain and opioid tolerance by sensitizing trigeminal ganglion (TG) cells, the main sensory neurons innervating the face and mouth. EGFR ligands were secreted by oral squamous cell carcinoma (OSCC) cells and by peripheral glial cells cocultured with OSCC cells. In human OSCC and an orthotopic mouse model, EGFR was abundant in tumor-innervating TG nerves. Oral cancer pain and opioid tolerance in the mice were increased by EGFR ligands and reduced by EGFR inhibitors. In mice, the abundance of glutamate-type NMDA receptors (NMDARs) was also increased in both the TG and the brainstem. Upon activation by ligands or OSCC cell supernatant, EGFR phosphorylated the NMDAR subunit GluN2B, which increased electrical currents and sensitized pre- and postsynaptic NMDARs in the brainstem. This sensitization was also seen in the brainstems of mice receiving chronic morphine treatment and was mitigated by EGFR blockade. These findings suggest that EGFR-targeted cancer therapeutics may be repurposed to manage cancer pain and reduce opioid tolerance in patients with OSCC.<\/jats:p>","DOI":"10.1126\/scisignal.adt3026","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T18:58:16Z","timestamp":1769540296000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":5,"title":["EGFR activation sensitizes trigeminal NMDA receptors to promote pain and morphine analgesic tolerance in oral cancer"],"prefix":"10.1126","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2477-7636","authenticated-orcid":true,"given":"Naijiang","family":"Liu","sequence":"first","affiliation":[{"name":"Translational Research Center, College of Dentistry, New York University, New York, NY 10010, USA."},{"name":"Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojie","family":"Shi","sequence":"additional","affiliation":[{"name":"Translational Research Center, College of Dentistry, New York University, New York, NY 10010, USA."},{"name":"Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0426-8202","authenticated-orcid":true,"given":"Shao-Rui","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Anesthesiology, Critical Care Medicine, and Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Anesthesiology, Critical Care Medicine, and Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3866-1424","authenticated-orcid":true,"given":"Maria Daniela","family":"Santi","sequence":"additional","affiliation":[{"name":"Translational Research Center, College of Dentistry, New York University, New York, NY 10010, USA."},{"name":"Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4639-9075","authenticated-orcid":true,"given":"Dong Minh","family":"Phuong","sequence":"additional","affiliation":[{"name":"Loma Linda University School of Dentistry, Loma Linda, CA 92350, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8899-2099","authenticated-orcid":true,"given":"Maria Fernanda Pessano","family":"Fialho","sequence":"additional","affiliation":[{"name":"Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongxin","family":"Xie","sequence":"additional","affiliation":[{"name":"Head &amp; Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7847-9902","authenticated-orcid":true,"given":"Frederico","family":"Gleber-Netto","sequence":"additional","affiliation":[{"name":"Head &amp; Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2737-8233","authenticated-orcid":true,"given":"Rocco","family":"Latorre","sequence":"additional","affiliation":[{"name":"Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3367-0644","authenticated-orcid":true,"given":"Nigel W.","family":"Bunnett","sequence":"additional","affiliation":[{"name":"Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA."},{"name":"Department of Neuroscience, Grossman School of Medicine, New York University, New York, NY 10010, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Viet","sequence":"additional","affiliation":[{"name":"Loma Linda University School of Dentistry, Loma Linda, CA 92350, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moran","family":"Amit","sequence":"additional","affiliation":[{"name":"Head &amp; Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8444-3770","authenticated-orcid":true,"given":"Hui-Lin","family":"Pan","sequence":"additional","affiliation":[{"name":"Division of Anesthesiology, Critical Care Medicine, and Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1075-5584","authenticated-orcid":true,"given":"Yi","family":"Ye","sequence":"additional","affiliation":[{"name":"Translational Research Center, College of Dentistry, New York University, New York, NY 10010, USA."},{"name":"Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA."},{"name":"Department of Biomedical Engineering, Tandon School of Engineering, New York University, New York, NY 10010, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005537-200104000-00021"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2007.06.012"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdm056"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fpain.2023.1146667"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2024.104615"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0885-3924(96)00302-8"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1177\/0022034511424156"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.789"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-017-9687-8"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2012.00409"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2013.10.002"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13112748"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sjpain.2012.11.012"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-018-0202-2"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/pm\/pnz101"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aev326"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI87406"},{"key":"e_1_3_2_19_2","first-page":"100371","article-title":"Association between EGFR and ALK mutation status on patient-reported symptoms after palliative radiation for bone pain in NSCLC","volume":"3","author":"Sit D.","year":"2022","unstructured":"D. Sit, M. Bale, V. Lapointe, R. Olson, F. Hsu, Association between EGFR and ALK mutation status on patient-reported symptoms after palliative radiation for bone pain in NSCLC. JTO Clin. Res. Rep. 3, 100371 (2022).","journal-title":"JTO Clin. Res. Rep."},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abe1648"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0460-18.2020"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sjpain.2012.11.011"},{"key":"e_1_3_2_23_2","doi-asserted-by":"crossref","first-page":"e0256870","DOI":"10.1371\/journal.pone.0256870","article-title":"Morphine promotes microglial activation by upregulating the EGFR\/ERK signaling pathway","volume":"16","author":"Yang Y.","year":"2021","unstructured":"Y. Yang, Y. Sun, R. Hu, J. Yan, Z. Wang, W. Li, H. Jiang, Morphine promotes microglial activation by upregulating the EGFR\/ERK signaling pathway. PLOS ONE 16, e0256870 (2021).","journal-title":"PLOS ONE"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2021.108703"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abj1531"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1097\/PR9.0000000000000718"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1177\/1744806919857297"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.3892\/or.2011.1616"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.240531027"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1186\/1748-717X-1-11"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-17-0333"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.3389\/fpain.2022.991725"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001926"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells12131675"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1186\/2051-5960-2-62"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001044"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03047-y"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.378737"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1586\/ecp.11.17"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0757-21.2021"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2015.07.021"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13826"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/356521a0"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0601-23.2023"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.003977"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1704-22.2022"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5857-09.2010"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP277428"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1177\/00220345221088527"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0183-23.2023"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.02.021"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-019-00618-2"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2022.05.003"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm12062156"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007461"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.14-04-02301.1994"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001792"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1302\/2046-3758.108.BJR-2019-0308.R2"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.104961"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1186\/1744-9081-10-5"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2018.07.016"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci13030390"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(94)90144-9"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejp.1528"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2013.12.010"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3032-17.2018"}],"container-title":["Science Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scisignal.adt3026","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T18:58:21Z","timestamp":1769540301000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scisignal.adt3026"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,27]]},"references-count":65,"journal-issue":{"issue":"922","published-print":{"date-parts":[[2026,1,27]]}},"alternative-id":["10.1126\/scisignal.adt3026"],"URL":"https:\/\/doi.org\/10.1126\/scisignal.adt3026","relation":{},"ISSN":["1945-0877","1937-9145"],"issn-type":[{"value":"1945-0877","type":"print"},{"value":"1937-9145","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,27]]},"assertion":[{"value":"2024-09-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-18","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadt3026"}}