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Focal adhesion kinase (FAK) and proline rich tyrosine kinase 2 (Pyk2) regulate proliferation and invasion of GBM cells. We found that TMZ activates FAK and Pyk2 signaling in GBM. We hypothesized that pharmacological inhibitors of Pyk2\/FAK together with TMZ can enhance the inhibitory effect of TMZ on tumor growth and dispersal and improve the treatment outcome.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Primary human GBM cell cultures and a C57Bl\/6-GL261 mouse glioma implantation model were used. Pyk2 (Tyr579\/580) and FAK (Tyr925) phosphorylation was analyzed by western blotting. Viability, cell cycle, migration, invasion and invadopodia formation were investigated in vitro. Animal survival, tumor size and invasion, TUNEL apoptotic cell death and the Ki67 proliferation index were evaluated in vivo upon treatment with TMZ (50\u00a0mg\/kg, once\/day, orally) and the Pyk2\/FAK inhibitor PF-562271 (once\/daily, 50\u00a0mg\/kg, orally) vs. TMZ monotherapy.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In vitro studies revealed significantly reduced viability, cell cycle progression, invasion and invadopodia with TMZ (100\u00a0\u00b5M)\u2009+\u2009PF-562271 (16\u00a0nM) compared with TMZ alone. In vivo studies demonstrated that combinatorial treatment led to prominent reductions in tumor size and invasive margins, extensive signs of apoptosis and a reduced proliferation index, together with a 15% increase in the survival rate in animals, compared with TMZ monotherapy.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>TMZ\u2009+\u2009PF-562271 eliminates TMZ-related Pyk2\/FAK activation in GBM and improves the treatment efficacy.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s11060-023-04260-3","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T21:14:04Z","timestamp":1677014044000},"page":"593-604","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The PYK2 inhibitor PF-562271 enhances the effect of temozolomide on tumor growth in a C57Bl\/6-Gl261 mouse glioma model"],"prefix":"10.1007","volume":"161","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6580-7425","authenticated-orcid":false,"given":"Jescelica","family":"Ortiz-Rivera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5731-6506","authenticated-orcid":false,"given":"Rebeca","family":"Nu\u00f1ez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6572-5139","authenticated-orcid":false,"given":"Yuriy","family":"Kucheryavykh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8053-5619","authenticated-orcid":false,"given":"Lilia","family":"Kucheryavykh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,2,15]]},"reference":[{"issue":"1","key":"4260_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11060-016-2096-y","volume":"128","author":"L Hamard","year":"2016","unstructured":"Hamard L, Ratel D, Selek L, Berger F, van der Sanden B, Wion D (2016) The brain tissue response to surgical injury and its possible contribution to glioma recurrence. 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All experimental procedures were carried out in accordance with the broad consent approved by the Institutional Review Board (IRB) Human Research Subject Protection Office (protocol #2012-12B, July 16, 2019). All procedures involving rodents were conducted in accordance with the National Institutes of Health regulations concerning the use and care of experimental animals. All procedures involving animals were approved by the Universidad Central del Caribe Institutional Animal Care and Use Committee (protocol #036\u20132020-24\u201301-PHA-IBC, September 22, 2020). All efforts were made to minimize suffering.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publications"}}]}}