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Beta1 integrins are known to contribute to cell adhesion-mediated drug resistance in cancer. Very late antigen-4 (VLA-4), a CD49d\/CD29 heterodimer, is a beta1 integrin implicated in therapy resistance in both solid tumors and haematological malignancies such as chronic lymphocytic leukemia (CLL). A complex inside-out signaling mechanism activates VLA-4, which might include several therapeutic targets for CLL. Treatment regimens for this disease have recently shifted towards novel agents targeting BCR signaling. Bruton\u2019s tyrosine kinase (BTK) is a component of B cell receptor signaling and BTK inhibitors such as ibrutinib are highly successful; however, their limitations include indefinite drug administration, the development of therapy resistance, and toxicities. VLA-4 might be activated independently of BTK, resulting in an ongoing interaction of CD49d-expressing leukemic cells with their surrounding tissue, which may reduce the success of therapy with BTK inhibitors and increases the need for alternative therapies. In this context, we discuss the inside-out signaling cascade culminating in VLA-4 activation, consider the advantages and disadvantages of BTK inhibitors in CLL and elucidate the mechanisms behind cell adhesion-mediated drug resistance.<\/jats:p>","DOI":"10.3390\/cells11142235","type":"journal-article","created":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T11:32:23Z","timestamp":1658143943000},"page":"2235","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Integrin Signaling Shaping BTK-Inhibitor Resistance"],"prefix":"10.3390","volume":"11","author":[{"given":"Laura","family":"Polcik","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I, Faculty of Medicine and Medical Center, University of Freiburg, 79106 Freiburg, Germany"},{"name":"Faculty of Biology, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"Dannewitz Prosseda","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Faculty of Medicine and Medical Center, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Pozzo","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3678-5957","authenticated-orcid":false,"given":"Antonella","family":"Zucchetto","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valter","family":"Gattei","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0377-7179","authenticated-orcid":false,"given":"Tanja Nicole","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Faculty of Medicine and Medical Center, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1007\/s11899-021-00645-1","article-title":"BTK inhibitors in chronic Lymphocytic Leukemia","volume":"16","author":"Gaballa","year":"2021","journal-title":"Curr. 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