{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T03:16:51Z","timestamp":1776309411967,"version":"3.50.1"},"reference-count":50,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T00:00:00Z","timestamp":1727049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ditmanson Medical Foundation Chia-Yi Christian Hospital"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Lung cancer remains a formidable health challenge due to its high mortality and morbidity rates. Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancer cases, with small cell lung cancer (SCLC) accounting for the remainder. Both NSCLC and SCLC cells express receptor tyrosine kinases, which may be overexpressed or mutated in lung cancer, leading to increased activation. The c-Met receptor tyrosine kinase, crucial for cell transformation and tumor growth, invasion, and metastasis, became the focus of our study. We used an E1B55KD-deleted, replication-selective oncolytic adenovirus (Ad.What), driven by the c-Met promoter, targeting lung cancer cells with c-Met overexpression, thus sparing normal cells. Previous studies have shown the enhanced antitumor efficacy of oncolytic adenoviruses when combined with chemotherapeutic agents. We explored combining rapamycin, a selective mTOR inhibitor with promising clinical trial outcomes for various cancers, with Ad.What. This combination increased infectivity by augmenting the expression of coxsackievirus and adenovirus receptors and \u03b1V integrin on cancer cells and induced autophagy. Our findings suggest that combining a c-Met promoter-driven oncolytic adenovirus with rapamycin could be an effective lung cancer treatment strategy, offering a targeted approach to exploit lung cancer cells\u2019 vulnerabilities, potentially marking a significant advancement in managing this deadly disease.<\/jats:p>","DOI":"10.3390\/cells13181597","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T03:49:46Z","timestamp":1727149786000},"page":"1597","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Advancing Lung Cancer Treatment with Combined c-Met Promoter-Driven Oncolytic Adenovirus and Rapamycin"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4929-855X","authenticated-orcid":false,"given":"Shih-Yao","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Nursing, College of Nursing, Chung Hwa University of Medical Technology, Tainan 71703, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2709-4134","authenticated-orcid":false,"given":"Chung-Teng","family":"Wang","sequence":"additional","affiliation":[{"name":"Tong Yuan Diabetes Center, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"},{"name":"Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7675-9561","authenticated-orcid":false,"given":"Tang-Hsiu","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeng-Liang","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao-Tien","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Ting","family":"Yen","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yau-Lin","family":"Tseng","sequence":"additional","affiliation":[{"name":"Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7821-9406","authenticated-orcid":false,"given":"Chao-Liang","family":"Wu","sequence":"additional","affiliation":[{"name":"Tong Yuan Diabetes Center, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"},{"name":"Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"},{"name":"Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia-Ming","family":"Chang","sequence":"additional","affiliation":[{"name":"Thoracic Division, Department of Surgery, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi 60002, Taiwan"},{"name":"Institute of Molecular Biology, National Chung Cheng University, Chiayi 62102, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2449-8547","authenticated-orcid":false,"given":"Ai-Li","family":"Shiau","sequence":"additional","affiliation":[{"name":"Tong Yuan Diabetes Center, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"},{"name":"Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/ijc.23605","article-title":"Lung cancer epigenetics and genetics","volume":"123","author":"Risch","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Budisan, L., Zanoaga, O., Braicu, C., Pirlog, R., Covaliu, B., Esanu, V., Korban, S.S., and Berindan-Neagoe, I. (2021). Links between infections, lung cancer, and the immune system. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179394"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/sj.mt.6300108","article-title":"History of oncolytic viruses: Genesis to genetic engineering","volume":"15","author":"Kelly","year":"2007","journal-title":"Mol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1126\/science.1851332","article-title":"Experimental therapy of human glioma by means of a genetically engineered virus mutant","volume":"252","author":"Martuza","year":"1991","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/nm0697-639","article-title":"ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents","volume":"3","author":"Heise","year":"1997","journal-title":"Nat. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"171","DOI":"10.2174\/1568009618666171129221503","article-title":"Oncorine, the World First Oncolytic Virus Medicine and its Update in China","volume":"18","author":"Liang","year":"2018","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1200\/JCO.2014.58.3377","article-title":"Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma","volume":"33","author":"Andtbacka","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.cell.2018.07.035","article-title":"Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy","volume":"174","author":"Ribas","year":"2018","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1007\/s40259-022-00553-7","article-title":"Teserpaturev\/G47Delta: First Approval","volume":"36","author":"Frampton","year":"2022","journal-title":"BioDrugs"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1038\/nrc1750","article-title":"Recent progress in the battle between oncolytic viruses and tumours","volume":"5","author":"Parato","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7763","DOI":"10.1038\/sj.onc.1209048","article-title":"Development of transcriptionally regulated oncolytic adenoviruses","volume":"24","author":"Ko","year":"2005","journal-title":"Oncogene"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4319","DOI":"10.1158\/0008-5472.CAN-04-0064","article-title":"Infectivity-enhanced cyclooxygenase-2-based conditionally replicative adenoviruses for esophageal adenocarcinoma treatment","volume":"64","author":"Davydova","year":"2004","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1158\/1078-0432.CCR-07-1047","article-title":"Tumor-selective replication of an oncolytic adenovirus carrying oct-3\/4 response elements in murine metastatic bladder cancer models","volume":"14","author":"Wu","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hu, C.Y., Hung, C.F., Chen, P.C., Hsu, J.Y., Wang, C.T., Lai, M.D., Tsai, Y.S., Shiau, A.L., Shieh, G.S., and Wu, C.L. (2023). Oct4 and Hypoxia Dual-Regulated Oncolytic Adenovirus Armed with shRNA-Targeting Dendritic Cell Immunoreceptor Exerts Potent Antitumor Activity against Bladder Cancer. Biomedicines, 11.","DOI":"10.3390\/biomedicines11102598"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/gt.2014.122","article-title":"Potent antitumor activity of Oct4 and hypoxia dual-regulated oncolytic adenovirus against bladder cancer","volume":"22","author":"Lu","year":"2015","journal-title":"Gene Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"38308","DOI":"10.18632\/oncotarget.5702","article-title":"Etoposide enhances antitumor efficacy of MDR1-driven oncolytic adenovirus through autoupregulation of the MDR1 promoter activity","volume":"6","author":"Su","year":"2015","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.2741\/2760","article-title":"The biological role of HGF-MET axis in tumor growth and development of metastasis","volume":"13","author":"Lesko","year":"2008","journal-title":"Front. Biosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s10555-007-9107-6","article-title":"The Met tyrosine kinase receptor in development and cancer","volume":"27","author":"Gentile","year":"2008","journal-title":"Cancer Metastasis Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"184","DOI":"10.18632\/oncotarget.26546","article-title":"Failures in preclinical and clinical trials of c-Met inhibitors: Evaluation of pathway activity as a promising selection criterion","volume":"10","author":"Hughes","year":"2019","journal-title":"Oncotarget"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.lungcan.2019.04.028","article-title":"c-MET as a biomarker in patients with surgically resected non-small cell lung cancer","volume":"133","author":"Tsakonas","year":"2019","journal-title":"Lung Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/s41591-019-0716-8","article-title":"Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration","volume":"26","author":"Drilon","year":"2020","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kim, N.A., Hong, S., Kim, K.H., Choi, D.H., Kim, J.S., Park, K.E., Choi, J.Y., Shin, Y.K., and Jeong, S.H. (2020). New Preclinical Development of a c-Met Inhibitor and Its Combined Anti-Tumor Effect in c-Met-Amplified NSCLC. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12020121"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/sj.clpt.6100317","article-title":"Rapamycin: Something old, something new, sometimes borrowed and now renewed","volume":"82","author":"Hartford","year":"2007","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1111\/1759-7714.12332","article-title":"Rapamycin-induced autophagy sensitizes A549 cells to radiation associated with DNA damage repair inhibition","volume":"7","author":"Li","year":"2016","journal-title":"Thorac. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1007\/s00432-020-03422-4","article-title":"Rapamycin inhibits lung squamous cell carcinoma growth by downregulating glypican-3\/Wnt\/\u03b2-catenin signaling and autophagy","volume":"147","author":"Bi","year":"2021","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"18223","DOI":"10.18632\/aging.203226","article-title":"Combination of rapamycin and SAHA enhanced radiosensitization by inducing autophagy and acetylation in NSCLC","volume":"13","author":"Wang","year":"2021","journal-title":"Aging"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0378-1119(98)00264-9","article-title":"The human hepatocyte growth factor receptor gene: Complete structural organization and promoter characterization","volume":"215","author":"Liu","year":"1998","journal-title":"Gene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3947","DOI":"10.1016\/S0264-410X(01)00130-X","article-title":"Prothymosin \u03b1 enhances protective immune responses induced by oral DNA vaccination against pseudorabies delivered by Salmonella choleraesuis","volume":"19","author":"Shiau","year":"2001","journal-title":"Vaccine"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/viro.2000.0468","article-title":"Cell receptors involved in adenovirus entry","volume":"274","author":"Nemerow","year":"2000","journal-title":"Virology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1038\/nrd2272","article-title":"Potential therapeutic applications of autophagy","volume":"6","author":"Rubinsztein","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12243","DOI":"10.1128\/JVI.78.22.12243-12251.2004","article-title":"Conditionally replicating adenoviruses kill tumor cells via a basic apoptotic machinery-independent mechanism that resembles necrosis-like programmed cell death","volume":"78","author":"Abbas","year":"2004","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"118","DOI":"10.4161\/auto.5260","article-title":"Adenovirus\u2019s last trick: You say lysis, we say autophagy","volume":"4","author":"Jiang","year":"2008","journal-title":"Autophagy"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Chen, T., Tu, S., Ding, L., Jin, M., Chen, H., and Zhou, H. (2023). The role of autophagy in viral infections. J. Biomed. Sci., 30.","DOI":"10.1186\/s12929-023-00899-2"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"110169","DOI":"10.1016\/j.clim.2024.110169","article-title":"From homeostasis to defense: Exploring the role of selective autophagy in innate immunity and viral infections","volume":"262","author":"Huang","year":"2024","journal-title":"Clin. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1093\/jnci\/djj161","article-title":"Autophagic cell death of malignant glioma cells induced by a conditionally replicating adenovirus","volume":"98","author":"Ito","year":"2006","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/sj.mt.6300400","article-title":"Delta-24-RGD in combination with RAD001 induces enhanced anti-glioma effect via autophagic cell death","volume":"16","author":"Alonso","year":"2008","journal-title":"Mol. Ther."},{"key":"ref_37","first-page":"3895","article-title":"Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells","volume":"56","author":"Seufferlein","year":"1996","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1007\/s11864-014-0313-5","article-title":"C-MET inhibitors in the treatment of lung cancer","volume":"15","author":"Spychalski","year":"2014","journal-title":"Curr. Treat. Options Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s11684-021-0869-y","article-title":"Rapamycin enhances the anti-tumor activity of cabozantinib in cMet inhibitor-resistant hepatocellular carcinoma","volume":"16","author":"Gao","year":"2022","journal-title":"Front. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1186\/1476-4598-13-185","article-title":"Combined targeting of mTOR and c-MET signaling pathways for effective management of epithelioid sarcoma","volume":"13","author":"Imura","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/0042-6822(87)90441-7","article-title":"Adenovirus proteins from both E1B reading frames are required for transformation of rodent cells by viral infection and DNA transfection","volume":"156","author":"Barker","year":"1987","journal-title":"Virology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"9470","DOI":"10.1128\/JVI.72.12.9470-9478.1998","article-title":"Replication of ONYX-015, a potential anticancer adenovirus, is independent of p53 status in tumor cells","volume":"72","author":"Rothmann","year":"1998","journal-title":"J. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"12483","DOI":"10.1128\/JVI.76.24.12483-12490.2002","article-title":"Evidence that replication of the antitumor adenovirus ONYX-015 is not controlled by the p53 and p14(ARF) tumor suppressor genes","volume":"76","author":"Edwards","year":"2002","journal-title":"J. Virol."},{"key":"ref_44","first-page":"5959","article-title":"p14(ARF) modulates the cytolytic effect of ONYX-015 in mesothelioma cells with wild-type p53","volume":"61","author":"Yang","year":"2001","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.ccr.2004.11.012","article-title":"Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity","volume":"6","author":"Johnson","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1182\/blood.V99.6.2248","article-title":"Histone deacetylase inhibitor FR901228 enhances adenovirus infection of hematopoietic cells","volume":"99","author":"Kitazono","year":"2002","journal-title":"Blood"},{"key":"ref_47","first-page":"6328","article-title":"Enhanced adenovirus transgene expression in malignant cells treated with the histone deacetylase inhibitor FR901228","volume":"61","author":"Kitazono","year":"2001","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"9957","DOI":"10.1158\/0008-5472.CAN-06-1138","article-title":"Low-dose etoposide enhances telomerase-dependent adenovirus-mediated cytosine deaminase gene therapy through augmentation of adenoviral infection and transgene expression in a syngeneic bladder tumor model","volume":"66","author":"Shieh","year":"2006","journal-title":"Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Folgiero, V., Avetrani, P., Bon, G., Di Carlo, S.E., Fabi, A., Nistico, C., Vici, P., Melucci, E., Buglioni, S., and Perracchio, L. (2008). Induction of ErbB-3 expression by alpha6beta4 integrin contributes to tamoxifen resistance in ERbeta1-negative breast carcinomas. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001592"},{"key":"ref_50","first-page":"660","article-title":"Increased adenoviral transduction efficacy in human laryngeal carcinoma cells resistant to cisplatin is associated with increased expression of integrin alphavbeta3 and coxsackie adenovirus receptor","volume":"110","author":"Gabrilovac","year":"2004","journal-title":"Int. J. Cancer"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/18\/1597\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:00:50Z","timestamp":1760112050000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/18\/1597"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,23]]},"references-count":50,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["cells13181597"],"URL":"https:\/\/doi.org\/10.3390\/cells13181597","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,23]]}}}