{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T01:59:31Z","timestamp":1780451971536,"version":"3.54.1"},"reference-count":31,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T00:00:00Z","timestamp":1663718400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Lorlatinib, a third\u2010generation anaplastic lymphoma kinase (ALK)\u2010tyrosine kinase inhibitor (TKI) with a broad coverage against <jats:italic>ALK<\/jats:italic> mutations, has demonstrated dramatic effects in patients with <jats:italic>ALK<\/jats:italic>\u2010rearranged lung cancer. The mechanisms of acquired resistance to lorlatinib by secondary <jats:italic>ALK<\/jats:italic> compound mutations have recently been reported; however, resistance mechanisms other than secondary mutations remain unclear. Here, we investigated the molecular mechanisms of the acquired resistance in <jats:italic>ALK<\/jats:italic>\u2010rearranged lung cancer cells in vitro. We established two different lorlatinib\u2010resistant <jats:italic>ALK<\/jats:italic>\u2010rearranged lung cancer cell lines (H3122LR and A925LLR) via long\u2010term administration of lorlatinib. These resistant cells did not harbor the secondary <jats:italic>ALK<\/jats:italic> mutations and showed cross\u2010resistance to the other kinds of ALK\u2010TKIs (crizotinib or alectinib) compared with the parental cells; however, these resistant cells overexpressed the phosphorylated human epidermal growth factor receptor 3 (HER3) protein and the ligand of HER3 (neuregulin 1; NRG1). Pharmacological inhibition of HER3 with pan\u2010HER inhibitors or genetic knockdown of <jats:italic>HER3<\/jats:italic> with siRNA resensitized H3122LR and A925LLR cells to lorlatinib in vitro, indicating that H3122LR and A925LLR acquired resistance by NRG1\/HER3 activation. These findings demonstrated that targeting NRG1\/HER3 is a potential novel therapeutic option for lorlatinib\u2010resistant <jats:italic>ALK<\/jats:italic>\u2010rearranged lung cancer.<\/jats:p>","DOI":"10.1111\/cas.15579","type":"journal-article","created":{"date-parts":[[2022,9,10]],"date-time":"2022-09-10T08:04:51Z","timestamp":1662797091000},"page":"164-173","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["<scp>Pan\u2010HER<\/scp> inhibitors overcome lorlatinib resistance caused by <scp>NRG1<\/scp>\/<scp>HER3<\/scp> activation in <scp><i>ALK<\/i><\/scp>\u2010rearranged lung cancer"],"prefix":"10.1111","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2414-8344","authenticated-orcid":false,"given":"Hirokazu","family":"Taniguchi","sequence":"first","affiliation":[{"name":"Department of Respiratory Medicine Nagasaki University Graduate School of Biomedical Sciences  Nagasaki 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Respiratory Medicine Nagasaki University Graduate School of Biomedical Sciences  Nagasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Imamura","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Nagasaki University Graduate School of Biomedical Sciences  Nagasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Gyotoku","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Nagasaki University Graduate School of Biomedical Sciences  Nagasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinnosuke","family":"Takemoto","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Nagasaki University Graduate School of Biomedical Sciences  Nagasaki 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