{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:57:45Z","timestamp":1753891065458,"version":"3.41.2"},"reference-count":17,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T00:00:00Z","timestamp":1718668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012542","name":"Sichuan Province Science and Technology Support Program","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012542","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Targeted therapy and immunotherapy are both important in the treatment of non-small-cell lung cancer (NSCLC). Accurate diagnose and precise treatment are key in achieving long survival of patients. <jats:italic>MET<\/jats:italic> fusion is a rare oncogenic factor, whose optimal detection and treatment are not well established. Here, we report on a 32-year-old female lung adenocarcinoma patient with positive PD-L1 and negative driver gene detected by DNA-based next-generation sequencing (NGS). A radical resection of the primary lesion after chemotherapy combined with PD-1 checkpoint inhibitor administration indicated primary immuno-resistance according to her pathological response and rapid relapse. A rare <jats:italic>CD47-MET<\/jats:italic> was detected by RNA-based NGS, which was confirmed by fluorescence <jats:italic>in situ<\/jats:italic> hybridization. Multiplex immunofluorescence revealed a PD-L1 related heterogeneous immunosuppressive microenvironment with little distribution of CD4+ T cells and CD8+ T cells. Savolitinib therapy resulted in a progression-free survival (PFS) of &amp;gt;12 months, until a new secondary resistance mutation in <jats:italic>MET<\/jats:italic> p.D1228H was detected by re-biopsy and joint DNA-RNA-based NGS after disease progression. In this case, <jats:italic>CD47-MET<\/jats:italic> fusion NSCLC was primarily resistant to immunotherapy, sensitive to savolitinib, and developed secondary <jats:italic>MET<\/jats:italic> p.D1228H mutation after targeted treatment. DNA-RNA-based NGS is useful in the detection of such molecular events and tracking of secondary mutations in drug resistance. To this end, DNA-RNA-based NGS may be of better value in guiding precise diagnosis and individualized treatment in this patient population.<\/jats:p>","DOI":"10.3389\/fimmu.2024.1386561","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T05:10:57Z","timestamp":1718687457000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Joint DNA-RNA-based NGS for diagnosis and treatment of a rare CD47-MET fusion lung adenocarcinoma which was immunoresistant and savoltinib-sensitive: a case report"],"prefix":"10.3389","volume":"15","author":[{"given":"Rulan","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanyang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuejiao","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiya","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiewei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"497","DOI":"10.6004\/jnccn.2022.0025","article-title":"Non-small cell lung cancer, version 3.2022, NCCN clinical practice guidelines in oncology","volume":"20","author":"Ettinger","year":"2022","journal-title":". J Natl Compr Canc Netw"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0377-z","article-title":"MET-dependent solid tumours - molecular diagnosis and targeted therapy","volume":"17","author":"Guo","year":"2020","journal-title":"Nat Rev Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20130432.CCR-17\u20133001","article-title":"Structural alterations of MET trigger response to MET kinase inhibition in lung adenocarcinoma patients","volume":"24","author":"Plenker","year":"2018","journal-title":"Clin Cancer Res"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20130432.CCR-19\u20130225","article-title":"High yield of RNA sequencing for targetable kinase fusions in lung adenocarcinomas with no mitogenic driver alteration detected by DNA sequencing and low tumor mutation burden","volume":"25","author":"Benayed","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2020.10.156","article-title":"Potential unreliability of uncommon ALK, ROS1, and RET genomic breakpoints in predicting the efficacy of targeted therapy in NSCLC","volume":"16","author":"Li","year":"2021","journal-title":"J Thorac Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20130432.CCR-19\u20131361","article-title":"Wake up and smell the fusions: single-modality molecular testing misses drivers","volume":"25","author":"Davies","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtocrr.2022.100276","article-title":"Performance of an RNA-based next-generation sequencing assay for combined detection of clinically actionable fusions and hotspot mutations in NSCLC","volume":"3","author":"Desmeules","year":"2022","journal-title":"JTO Clin Res Rep"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20138290.CD-20\u20131500","article-title":"MET amplification attenuates lung tumor response to immunotherapy by inhibiting STING","volume":"11","author":"Zhang","year":"2021","journal-title":"Cancer Discovery"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr-21\u2013124","article-title":"Has programmed cell death ligand-1 MET an accomplice in non-small cell lung cancer?-a narrative review","volume":"10","author":"Dempke","year":"2021","journal-title":"Transl Lung Cancer Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2020.11785","article-title":"Increase in CD4(+)FOXP3(+) regulatory T cell number and upregulation of the HGF\/c-Met signaling pathway during the liver metastasis of colorectal cancer","volume":"20","author":"Huang","year":"2020","journal-title":"Oncol Lett"},{"key":"B11","doi-asserted-by":"publisher","first-page":"5562","DOI":"10.3390\/cancers13215562","article-title":"Targeting HGF\/c-met axis decreases circulating regulatory T cells accumulation in gastric cancer patients","volume":"13","author":"Palle","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.02135","article-title":"HGF-MET signaling shifts M1 macrophages toward an M2-like phenotype through PI3K-mediated induction of arginase-1 expression","volume":"11","author":"Nishikoba","year":"2020","journal-title":"Front Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s12943\u2013021-01343\u20135","article-title":"Epigenetic silencing of miR-144\/451a cluster contributes to HCC progression via paracrine HGF\/MIF-mediated TAM remodeling","volume":"20","author":"Zhao","year":"2021","journal-title":"Mol Cancer"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2019.06.023","article-title":"Sensitivity and resistance of MET exon 14 mutations in lung cancer to eight MET tyrosine kinase inhibitors in vitro","volume":"14","author":"Fujino","year":"2019","journal-title":"J Thorac Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtocrr.2020.100071","article-title":"Acquired resistance to osimertinib plus savolitinib is mediated by MET-D1228 and MET-Y1230 mutations in EGFR-mutated MET-amplified lung cancer","volume":"1","author":"Piper-Vallillo","year":"2020","journal-title":"JTO Clin Res Rep"},{"key":"B16","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.lungcan.2023.01.017","article-title":"Response and acquired resistance to MET inhibitors in de novo MET fusion-positive advanced non-small cell lung cancer","volume":"178","author":"Kang","year":"2023","journal-title":"Lung Cancer"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1200\/PO.21.00076","article-title":"Overcoming acquired resistance mutation MET D1228N to crizotinib with cabozantinib in NSCLC with MET exon 14 skipping mutation","volume":"5","author":"Pruis","year":"2021","journal-title":"JCO Precis Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1386561\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T05:11:02Z","timestamp":1718687462000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1386561\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,18]]},"references-count":17,"alternative-id":["10.3389\/fimmu.2024.1386561"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1386561","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2024,6,18]]},"article-number":"1386561"}}