{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:37:34Z","timestamp":1791434254140,"version":"4.3.3"},"reference-count":88,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA292653"],"award-info":[{"award-number":["R01CA292653"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30CA240139"],"award-info":[{"award-number":["P30CA240139"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sylvester Comprehensive Cancer Center","award":["R01CA292653"],"award-info":[{"award-number":["R01CA292653"]}]},{"name":"Sylvester Comprehensive Cancer Center","award":["P30CA240139"],"award-info":[{"award-number":["P30CA240139"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western populations and remains incurable despite significant therapeutic advancements. Over the past decade, the treatment landscape has evolved from traditional chemoimmunotherapy to targeted oral agents, including Bruton\u2019s tyrosine kinase inhibitors (BTKis) and BCL2 inhibitors (BCL2is), which have demonstrated superior efficacy and tolerability, especially in elderly patients. Venetoclax, a BCL2i, induces apoptosis in CLL cells through selective inhibition of the anti-apoptotic BCL2 protein, while BTKis, such as ibrutinib and its next-generation analogs, disrupt B-cell receptor signaling critical to CLL cell survival. However, resistance to both drug classes has emerged, including mutations in BTK and BCL2, prompting the exploration of novel therapeutic strategies. This review outlines the molecular basis and clinical implications of these resistance mechanisms, as well as emerging therapeutic solutions, including non-covalent BTKis like pirtobrutinib and BTK-targeting PROTAC degraders such as BGB-16673 and NX-2127. Additionally, we discuss promising combination therapies incorporating BTKis, BCL2is, and anti-CD20 monoclonal antibodies. Finally, we highlight the growing role of measurable residual disease (MRD) as a biomarker to guide treatment duration and evaluate therapeutic success. As resistance mechanisms continue to emerge, tailoring therapy based on underlying biology will be critical to sustaining disease control and enhancing outcomes in patients with CLL.<\/jats:p>","DOI":"10.3390\/genes16091064","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T10:27:12Z","timestamp":1757500032000},"page":"1064","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Resistance Mutations in CLL: Genetic Mechanisms Shaping the Future of Targeted Therapy"],"prefix":"10.3390","volume":"16","author":[{"given":"Samantha","family":"Sekeres","sequence":"first","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"College of Engineering, University of Miami, Miami, FL 33146, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2404-5129","authenticated-orcid":false,"given":"Erica N.","family":"Lamkin","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Medical Scientist Training Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8560-287X","authenticated-orcid":false,"suffix":"Jr.","given":"Eduardo","family":"Bravo","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0424-080X","authenticated-orcid":false,"given":"Allison","family":"Cool","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4407-6325","authenticated-orcid":false,"given":"Justin","family":"Taylor","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1182\/asheducation-2005.1.278","article-title":"CLL Biology and Prognosis","volume":"2005","author":"Dighiero","year":"2005","journal-title":"Hematology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1002\/ajh.24282","article-title":"Chronic lymphocytic leukemia (CLL)\u2014Then and now","volume":"91","author":"Rai","year":"2016","journal-title":"Am. 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