{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T03:30:37Z","timestamp":1786332637626,"version":"build-2736575974"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Intravesical interferon-alpha (IFN\u03b1) gene therapy is approved by the FDA for BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). Identifying resistance mechanisms and deploying targeted combination treatment strategies is a rational approach to improving treatment responses. We identified the ErbB pathway as a resistance mechanism to IFN\u03b1 gene therapy, and we hypothesized that combination treatment with an ErbB pathway blocker and IFN-\u03b1 could improve outcomes in resistant tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Murine bladder cancer cells were treated\n                      <jats:italic>in vitro<\/jats:italic>\n                      with lentiviral IFN\u03b1 (LV-IFN\u03b1) gene therapy, with\/without afatinib (Afa), a pan-ErbB inhibitor, and cell viability and migration assays were performed.\n                      <jats:italic>In vivo<\/jats:italic>\n                      studies were conducted in a syngeneic MB49 orthotopic murine bladder cancer model, and mice were randomized into five treatment groups and treated with single treatments: Ctrl (vehicle), LV-Ctrl, LV-IFN\u03b1, and combination treatments with LV-Ctrl\/Afa or LV-IFN\u03b1\/Afa.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Combination therapy with LV-IFN\u03b1\/Afa significantly reduced MB49 cell viability\n                      <jats:italic>in vitro<\/jats:italic>\n                      compared to all other treatment conditions. This additive effect on cell viability appeared to be driven by a combination of early-cytostatic and late-cytolytic effects. The combination treatment also markedly inhibited cell migration. Finally, the\n                      <jats:italic>in vivo<\/jats:italic>\n                      studies demonstrated improved overall survival (OS) with LV-IFN\u03b1\/Afa (median OS was 49 days in the LV-IFN\u03b1\/Afa group vs. 15, 14, 29, and 26 days in Ctrl, LV-Ctrl, LV-IFN\u03b1, and LV-Ctrl\/Afa groups, respectively; log-rank\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings suggest that the ErbB pathway may serve as a clinically actionable resistance mechanism to intravesical IFN\u03b1 gene therapy and, when targeted concurrently, it may improve treatment efficacy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmolb.2026.1804161","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T03:26:15Z","timestamp":1786332375000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Combination treatment with intravesical interferon-alpha gene therapy and an oral pan-ErbB receptor family blocker improves survival in mice with bladder cancer"],"prefix":"10.3389","volume":"13","author":[{"given":"Akshay","family":"Sood","sequence":"first","affiliation":[{"name":"Department of Urology and Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]},{"name":"Department of Urology, The James Cancer Hospital and Solove Research Institute, The Ohio State University Wexner Medical Center","place":["Columbus, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Martini","sequence":"additional","affiliation":[{"name":"Department of Urology and Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo","family":"Genitiano","sequence":"additional","affiliation":[{"name":"Department of Urology and Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikael","family":"Rauf","sequence":"additional","affiliation":[{"name":"Department of Urology and Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganiraju","family":"Manyam","sequence":"additional","affiliation":[{"name":"Department of Urology and Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan K.","family":"Rudzinski","sequence":"additional","affiliation":[{"name":"Department of Urology and Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Come","family":"Tholomier","sequence":"additional","affiliation":[{"name":"Department of Urology and Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Contieri","sequence":"additional","affiliation":[{"name":"Department of Urology and Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Ling","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Urology and Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel R.","family":"Parker","sequence":"additional","affiliation":[{"name":"A.I. 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