{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T22:21:19Z","timestamp":1788992479408,"version":"build-2803163510"},"reference-count":57,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Indiana University Medical Student Program for Research and Scholarship"},{"name":"University of Notre Dame College of Science Summer Undergraduate Research Fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Combination chemotherapy regimens are commonly employed to treat advanced gastric adenocarcinoma (GAC), yet median survival remains less than one year. Nab-paclitaxel has demonstrated significant antitumor activity in preclinical GAC models. Overexpression of growth factors and their receptors is prevalent in GAC and contributes to its pathophysiology, with aberrant activation of the HGF\/c-Met pathway reported in up to 50% of patients. We hypothesized that merestinib, a small-molecule inhibitor of c-Met, Axl, and DDR1\/2, would enhance the therapeutic response to nab-paclitaxel in GAC. In high c-Met\u2013expressing MKN-45 peritoneal dissemination xenografts in female NOD\/SCID mouse models, animal survival was 17 days in controls, 37 days with nab-paclitaxel (118% increase), 24 days with merestinib (41% increase), and 43 days with the combination (153% increase), demonstrating significantly enhanced survival compared with either monotherapy. In MKN-45 subcutaneous xenografts, tumor volumes in the control, nab-paclitaxel, merestinib, and combination groups were 503 mm3, 115 mm3, 91 mm3, and \u22129.7 mm3 (indicating tumor regression), respectively. In low c-Met-expressing SNU-1 xenografts, tumor volumes were 219 mm3, 105 mm3, 131 mm3, and 57 mm3, respectively. IHC analysis of tumor cell proliferation and microvessel density in MKN-45 tumors supported these findings. In vitro, nab-paclitaxel and merestinib each reduced cell proliferation in GAC-associated cells, with enhanced inhibitory effects when used in combination. In MKN-45 cells, merestinib increased the expression of pro-apoptotic proteins and decreased phosphorylation of c-Met, EGFR, IGF-1R, ERK, and AKT. These results indicate that combining merestinib with nab-paclitaxel may represent a promising therapeutic strategy to improve outcomes for patients with GAC.<\/jats:p>","DOI":"10.3390\/cells15030285","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T09:00:58Z","timestamp":1770109258000},"page":"285","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting the c-Met\/VEGFR Pathway to Boost Nab-Paclitaxel Efficacy in Gastric Cancer: Preclinical Insights"],"prefix":"10.3390","volume":"15","author":[{"given":"Jennifer","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4974-898X","authenticated-orcid":false,"given":"Quinn","family":"Kaurich","sequence":"additional","affiliation":[{"name":"Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6309-9616","authenticated-orcid":false,"given":"Md Sazzad","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA"},{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urs","family":"von Holzen","sequence":"additional","affiliation":[{"name":"Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA"},{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA"},{"name":"Goshen Center for Cancer Care, Goshen, IN 46526, USA"},{"name":"School of Medicine, University of Basel, CH-4056 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niranjan","family":"Awasthi","sequence":"additional","affiliation":[{"name":"Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA"},{"name":"Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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