{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:02:23Z","timestamp":1790089343486,"version":"4.0.1"},"reference-count":84,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T00:00:00Z","timestamp":1728518400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>B-cell lymphoid malignancies are a heterogeneous group of hematologic cancers, where Bruton\u2019s tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling. Resistance to covalent BTK inhibitors (BTKi) can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLC\u03b32) resulting in downstream signaling. To bypass the C481S mutation, non-covalent BTKi, such as Pirtobrutinib, were developed and are active against both wild-type and the C481S mutation. In this review, we discuss the molecular and genetic mechanisms which contribute to acquisition of resistance to covalent and non-covalent BTKi. In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTKi and the development of new therapeutic strategies highlight the ongoing advances being made towards the pursuit of a cure for B-cell lymphoid malignancies.<\/jats:p>","DOI":"10.3390\/cancers16203434","type":"journal-article","created":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T07:54:09Z","timestamp":1728546849000},"page":"3434","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Advances in Targeted Therapy: Addressing Resistance to BTK Inhibition in B-Cell Lymphoid Malignancies"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6744-8529","authenticated-orcid":false,"given":"Andres","family":"Bravo-Gonzalez","sequence":"first","affiliation":[{"name":"London School of Hygiene and Tropical Medicine, Bogot\u00e1 110221, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8377-2422","authenticated-orcid":false,"given":"Maryam","family":"Alasfour","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Miami and Jackson Memorial Hospital, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Soong","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Miami and Jackson Memorial Hospital, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Noy","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Miami and Jackson Memorial Hospital, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6594-8682","authenticated-orcid":false,"given":"Georgios","family":"Pongas","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, University of Miami and Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"443","DOI":"10.3322\/caac.21357","article-title":"2016 US Lymphoid Malignancy Statistics by World Health Organization Subtypes","volume":"66","author":"Teras","year":"2016","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1111\/imm.13416","article-title":"The Role of Bruton\u2019s Tyrosine Kinase in the Immune System and Disease","volume":"164","author":"McDonald","year":"2021","journal-title":"Immunology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1002\/cmdc.200600221","article-title":"Discovery of Selective Irreversible Inhibitors for Bruton\u2019s Tyrosine Kinase","volume":"2","author":"Pan","year":"2007","journal-title":"ChemMedChem"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1182\/blood.2019000854","article-title":"Prevalence of BTK and PLCG2 Mutations in a Real-Life CLL Cohort Still on Ibrutinib after 3 Years: A FILO Group Study","volume":"134","author":"Quinquenel","year":"2019","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1182\/blood-2021-149138","article-title":"Pirtobrutinib, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated Mantle Cell Lymphoma: Updated Results from the Phase 1\/2 BRUIN Study","volume":"138","author":"Wang","year":"2021","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/S0140-6736(21)00224-5","article-title":"Pirtobrutinib in Relapsed or Refractory B-Cell Malignancies (BRUIN): A Phase 1\/2 Study","volume":"397","author":"Mato","year":"2021","journal-title":"The Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"eadi5798","DOI":"10.1126\/science.adi5798","article-title":"Kinase-Impaired BTK Mutations Are Susceptible to Clinical-Stage BTK and IKZF1\/3 Degrader NX-2127","volume":"383","author":"Montoya","year":"2024","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1542\/peds.9.6.722","article-title":"Agammaglobulinemia","volume":"9","author":"Bruton","year":"1952","journal-title":"Pediatrics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/361226a0","article-title":"The Gene Involved in X-Linked Agammaglobulinaemia Is a Member of the Src Family of Protein-Tyrosine Kinases","volume":"361","author":"Vetrie","year":"1993","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/0092-8674(93)90667-F","article-title":"Deficient Expression of a B Cell Cytoplasmic Tyrosine Kinase in Human X-Linked Agammaglobulinemia","volume":"72","author":"Tsukada","year":"1993","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/1074-7613(95)90114-0","article-title":"Defective B Cell Development and Function in Btk-Deficient Mice","volume":"3","author":"Khan","year":"1995","journal-title":"Immunity"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1111\/j.1600-065X.2008.00741.x","article-title":"Bruton\u2019s Tyrosine Kinase (Btk): Function, Regulation, and Transformation with Special Emphasis on the PH Domain","volume":"228","author":"Mohamed","year":"2009","journal-title":"Immunol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1126\/science.271.5250.822","article-title":"Activation of BTK by a Phosphorylation Mechanism Initiated by SRC Family Kinases","volume":"271","author":"Rawlings","year":"1996","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S1074-7613(00)80417-3","article-title":"Regulation of Btk Function by a Major Autophosphorylation Site within the SH3 Domain","volume":"4","author":"Park","year":"1996","journal-title":"Immunity"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1182\/bloodadvances.2024012706","article-title":"In BTK, Phosphorylated Y223 in the SH3 Domain Mirrors Catalytic Activity, but Does Not Influence Biological Function","volume":"8","author":"Bouderlique","year":"2024","journal-title":"Blood Adv."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/S0092-8674(00)80373-6","article-title":"In Vivo Ablation of Surface Immunoglobulin on Mature B Cells by Inducible Gene Targeting Results in Rapid Cell Death","volume":"90","author":"Lam","year":"1997","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1016\/S1097-2765(02)00739-6","article-title":"Amplification of B Cell Antigen Receptor Signaling by a Syk\/ITAM Positive Feedback Loop","volume":"10","author":"Rolli","year":"2002","journal-title":"Mol. Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9986","DOI":"10.1128\/MCB.24.22.9986-9999.2004","article-title":"Mechanism of B-Cell Receptor-Induced Phosphorylation and Activation of Phospholipase C-Gamma2","volume":"24","author":"Kim","year":"2004","journal-title":"Mol. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1084\/jem.191.10.1735","article-title":"Bruton\u2019s Tyrosine Kinase Links the B Cell Receptor to Nuclear Factor kappaB Activation","volume":"191","author":"Bajpai","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nature08638","article-title":"Chronic Active B-Cell-Receptor Signalling in Diffuse Large B-Cell Lymphoma","volume":"463","author":"Davis","year":"2010","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13075","DOI":"10.1073\/pnas.1004594107","article-title":"The Bruton Tyrosine Kinase Inhibitor PCI-32765 Blocks B-Cell Activation and Is Efficacious in Models of Autoimmune Disease and B-Cell Malignancy","volume":"107","author":"Honigberg","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6287","DOI":"10.1182\/blood-2011-01-328484","article-title":"Bruton Tyrosine Kinase Represents a Promising Therapeutic Target for Treatment of Chronic Lymphocytic Leukemia and Is Effectively Targeted by PCI-32765","volume":"117","author":"Herman","year":"2011","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1200\/JCO.2012.42.7906","article-title":"Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients with Relapsed\/Refractory B-Cell Malignancies","volume":"31","author":"Advani","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1056\/NEJMoa1306220","article-title":"Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma","volume":"369","author":"Wang","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1182\/blood-2015-03-635326","article-title":"Long-Term Follow-up of MCL Patients Treated with Single-Agent Ibrutinib: Updated Safety and Efficacy Results","volume":"126","author":"Wang","year":"2015","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1056\/NEJMoa1400376","article-title":"Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia","volume":"371","author":"Coutre","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1002\/ajh.25638","article-title":"Final Analysis from RESONATE: Up to Six Years of Follow-up on Ibrutinib in Patients with Previously Treated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma","volume":"94","author":"Munir","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1056\/NEJMoa1501548","article-title":"Ibrutinib in Previously Treated Waldenstr\u00f6m\u2019s Macroglobulinemia","volume":"372","author":"Treon","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1200\/JCO.20.00555","article-title":"Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients With Waldenstr\u00f6m Macroglobulinemia","volume":"39","author":"Treon","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1038\/s41375-021-01417-9","article-title":"Long-Term Follow-up of Ibrutinib Monotherapy in Treatment-Naive Patients with Waldenstrom Macroglobulinemia","volume":"36","author":"Castillo","year":"2022","journal-title":"Leukemia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1038\/nm.3884","article-title":"Targeting B Cell Receptor Signaling with Ibrutinib in Diffuse Large B Cell Lymphoma","volume":"21","author":"Wilson","year":"2015","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1200\/JCO.18.02403","article-title":"Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma","volume":"37","author":"Younes","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2762","DOI":"10.1038\/s41375-019-0575-9","article-title":"Durable Response with Single-Agent Acalabrutinib in Patients with Relapsed or Refractory Mantle Cell Lymphoma","volume":"33","author":"Wang","year":"2019","journal-title":"Leukemia"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/S0140-6736(17)33108-2","article-title":"Acalabrutinib in Relapsed or Refractory Mantle Cell Lymphoma (ACE-LY-004): A Single-Arm, Multicentre, Phase 2 Trial","volume":"391","author":"Wang","year":"2018","journal-title":"Lancet"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/S0140-6736(20)30262-2","article-title":"Acalabrutinib with or without Obinutuzumab versus Chlorambucil and Obinutuzmab for Treatment-Naive Chronic Lymphocytic Leukaemia (ELEVATE TN): A Randomised, Controlled, Phase 3 Trial","volume":"395","author":"harman","year":"2020","journal-title":"Lancet"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1038\/s41375-021-01485-x","article-title":"Efficacy and Safety in a 4-Year Follow-up of the ELEVATE-TN Study Comparing Acalabrutinib with or without Obinutuzumab versus Obinutuzumab plus Chlorambucil in Treatment-Na\u00efve Chronic Lymphocytic Leukemia","volume":"36","author":"Sharman","year":"2022","journal-title":"Leukemia"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1182\/blood-2023-174750","article-title":"Acalabrutinib \u00b1 Obinutuzumab Vs Obinutuzumab + Chlorambucil in Treatment-Naive Chronic Lymphocytic Leukemia: 6-Year Follow-up of Elevate-TN","volume":"142","author":"Sharman","year":"2023","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e801","DOI":"10.1097\/HS9.0000000000000801","article-title":"Acalabrutinib Versus Investigator\u2019s Choice in Relapsed\/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results","volume":"6","author":"Ghia","year":"2022","journal-title":"Hemasphere"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1200\/JCO.19.03355","article-title":"ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia","volume":"38","author":"Ghia","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3148","DOI":"10.1182\/blood.2021014162","article-title":"Zanubrutinib in Relapsed\/Refractory Mantle Cell Lymphoma: Long-Term Efficacy and Safety Results from a Phase 2 Study","volume":"139","author":"Song","year":"2022","journal-title":"Blood"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3472","DOI":"10.1182\/bloodadvances.2021006083","article-title":"Zanubrutinib Monotherapy in Relapsed\/Refractory Indolent Non-Hodgkin Lymphoma","volume":"6","author":"Phillips","year":"2022","journal-title":"Blood Adv."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.1200\/JCO.22.02830","article-title":"Zanubrutinib Versus Ibrutinib in Symptomatic Waldenstr\u00f6m Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study","volume":"41","author":"Dimopoulos","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6323","DOI":"10.1158\/1078-0432.CCR-21-1704","article-title":"The MAGNOLIA Trial: Zanubrutinib, a Next-Generation Bruton Tyrosine Kinase Inhibitor, Demonstrates Safety and Efficacy in Relapsed\/Refractory Marginal Zone Lymphoma","volume":"27","author":"Opat","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/S1470-2045(22)00293-5","article-title":"Zanubrutinib versus Bendamustine and Rituximab in Untreated Chronic Lymphocytic Leukaemia and Small Lymphocytic Lymphoma (SEQUOIA): A Randomised, Controlled, Phase 3 Trial","volume":"23","author":"Tam","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1056\/NEJMoa2211582","article-title":"Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia","volume":"388","author":"Brown","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5107","DOI":"10.1200\/JCO.23.00775","article-title":"ROSEWOOD: A Phase II Randomized Study of Zanubrutinib Plus Obinutuzumab Versus Obinutuzumab Monotherapy in Patients With Relapsed or Refractory Follicular Lymphoma","volume":"41","author":"Zinzani","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1182\/blood-2020-134824","article-title":"Acalabrutinib Monotherapy in Patients with Relapsed\/Refractory Mantle Cell Lymphoma: Long-Term Efficacy and Safety Results from a Phase 2 Study","volume":"136","author":"Wang","year":"2020","journal-title":"Blood"},{"key":"ref_48","unstructured":"U.S. Food and Drug Administration (2021). FDA Approves Zanubrutinib for Waldenstr\u00f6m\u2019s Macroglobulinemia."},{"key":"ref_49","unstructured":"U.S. Food and Drug Administration (2022). FDA Grants Accelerated Approval to Zanubrutinib for Marginal Zone Lymphoma."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1182\/asheducation-2015.1.355","article-title":"Patterns of Resistance to B Cell-Receptor Pathway Antagonists in Chronic Lymphocytic Leukemia and Strategies for Management","volume":"2015","author":"Woyach","year":"2015","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1182\/blood-2016-06-719294","article-title":"Clonal Evolution Leading to Ibrutinib Resistance in Chronic Lymphocytic Leukemia","volume":"129","author":"Ahn","year":"2017","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1002\/jha2.891","article-title":"Richter Transformation Acquiring PLCG2 Mutation during Bruton Tyrosine Kinase Inhibitors Treatment","volume":"5","author":"Tsushima","year":"2024","journal-title":"EJHaem"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5589","DOI":"10.1182\/bloodadvances.2022008325","article-title":"Enrichment of BTK Leu528Trp Mutations in Patients with CLL on Zanubrutinib: Potential for Pirtobrutinib Cross-Resistance","volume":"6","author":"Blombery","year":"2022","journal-title":"Blood Adv."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1038\/leu.2017.110","article-title":"PLCG2 C2 Domain Mutations Co-Occur with BTK and PLCG2 Resistance Mutations in Chronic Lymphocytic Leukemia Undergoing Ibrutinib Treatment","volume":"31","author":"Jones","year":"2017","journal-title":"Leukemia"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Sedlarikova, L., Petrackova, A., Papajik, T., Turcsanyi, P., and Kriegova, E. (2020). Resistance-Associated Mutations in Chronic Lymphocytic Leukemia Patients Treated With Novel Agents. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.00894"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1001\/jamaoncol.2014.218","article-title":"Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia","volume":"1","author":"Maddocks","year":"2015","journal-title":"JAMA Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1182\/blood.2020006783","article-title":"Resistance to Bruton Tyrosine Kinase Inhibitors: The Achilles Heel of Their Success Story in Lymphoid Malignancies","volume":"138","author":"Stephens","year":"2021","journal-title":"Blood"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Brown, J., Mashima, K., Fernandes, S., Naeem, A., Shupe, S., Fardoun, R., and Davids, M. (2024). Mutations Detected in Real World Clinical Sequencing during BTK Inhibitor Treatment in CLL. Res. Sq., rs.3.rs-3837426.","DOI":"10.21203\/rs.3.rs-3837426\/v1"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1182\/blood.2023023659","article-title":"Mutational Profile of Previously Treated Chronic Lymphocytic Leukemia Patients Progressing on Acalabrutinib or Ibrutinib","volume":"144","author":"Woyach","year":"2024","journal-title":"Blood"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1056\/NEJMoa1400029","article-title":"Resistance Mechanisms for the Bruton\u2019s Tyrosine Kinase Inhibitor Ibrutinib","volume":"370","author":"Woyach","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"11589","DOI":"10.1038\/ncomms11589","article-title":"Clonal Evolution in Patients with Chronic Lymphocytic Leukaemia Developing Resistance to BTK Inhibition","volume":"7","author":"Burger","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3531","DOI":"10.1182\/bloodadvances.2022009412","article-title":"Molecular Associations of Response to the New-Generation BTK Inhibitor Zanubrutinib in Marginal Zone Lymphoma","volume":"7","author":"Tatarczuch","year":"2023","journal-title":"Blood Adv."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"835","DOI":"10.3324\/haematol.2024.285151","article-title":"Ultra-Deep Mutational Landscape in Chronic Lymphocytic Leukemia Uncovers Dynamics of Resistance to Targeted Therapies","volume":"109","author":"Woolston","year":"2024","journal-title":"Haematologica"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1182\/blood-2015-02-626846","article-title":"Hypermorphic Mutation of Phospholipase C, \u03932 Acquired in Ibrutinib-Resistant CLL Confers BTK Independency upon B-Cell Receptor Activation","volume":"126","author":"Liu","year":"2015","journal-title":"Blood"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"22136","DOI":"10.1074\/jbc.M116.746842","article-title":"The Phospholipase C\u03b32 Mutants R665W and L845F Identified in Ibrutinib-Resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein","volume":"291","author":"Walliser","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1038\/s41467-017-02329-y","article-title":"The Evolutionary Landscape of Chronic Lymphocytic Leukemia Treated with Ibrutinib Targeted Therapy","volume":"8","author":"Landau","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2927","DOI":"10.1182\/bloodadvances.2019001350","article-title":"Genetic Mutations and Features of Mantle Cell Lymphoma: A Systematic Review and Meta-Analysis","volume":"4","author":"Hill","year":"2020","journal-title":"Blood Adv"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/nm.3435","article-title":"Pharmacological and Genomic Profiling Identifies NF-\u03baB-Targeted Treatment Strategies for Mantle Cell Lymphoma","volume":"20","author":"Rahal","year":"2014","journal-title":"Nat. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/bjh.18418","article-title":"Resistance to Bruton Tyrosine Kinase Inhibition in Chronic Lymphocytic Leukaemia and Non-Hodgkin Lymphoma","volume":"200","author":"Nakhoda","year":"2023","journal-title":"Br. J. Haematol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1158\/2643-3230.BCD-21-0063","article-title":"Overcoming Acquired Epigenetic Resistance to BTK Inhibitors","volume":"2","author":"Shaffer","year":"2021","journal-title":"Blood Cancer Discov."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"14920","DOI":"10.1038\/ncomms14920","article-title":"Unification of de Novo and Acquired Ibrutinib Resistance in Mantle Cell Lymphoma","volume":"8","author":"Zhao","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1182\/bloodadvances.2016004176","article-title":"Microenvironmental Agonists Generate de Novo Phenotypic Resistance to Combined Ibrutinib plus Venetoclax in CLL and MCL","volume":"1","author":"Jayappa","year":"2017","journal-title":"Blood Adv."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1158\/2159-8290.CD-17-1409","article-title":"The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation","volume":"8","author":"Reiff","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1056\/NEJMoa2300696","article-title":"Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia","volume":"389","author":"Mato","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1158\/2159-8290.CD-23-0670","article-title":"First-in-Human Study of the Reversible BTK Inhibitor Nemtabrutinib in Patients with Relapsed\/Refractory Chronic Lymphocytic Leukemia and B-Cell Non\u2013Hodgkin Lymphoma","volume":"14","author":"Woyach","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"TPS7088","DOI":"10.1200\/JCO.2024.42.16_suppl.TPS7088","article-title":"BELLWAVE-011: Phase 3 Randomized Trial of Nemtabrutinib versus Ibrutinib or Acalabrutinib in Untreated Chronic Lymphocytic Leukemia\/Small Lymphocytic Lymphoma","volume":"42","author":"Tadmor","year":"2024","journal-title":"JCO"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1056\/NEJMoa2114110","article-title":"Mechanisms of Resistance to Noncovalent Bruton\u2019s Tyrosine Kinase Inhibitors","volume":"386","author":"Wang","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"(2022). On-Target BTK Mutations Promote Resistance to Noncovalent BTK Inhibitors. Cancer Discovery, 12, 1179.","DOI":"10.1158\/2159-8290.CD-RW2022-041"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1182\/blood-2018-07-862953","article-title":"Bruton Tyrosine Kinase Degradation as a Therapeutic Strategy for Cancer","volume":"133","author":"Dobrovolsky","year":"2019","journal-title":"Blood"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1021\/acs.jmedchem.3c01007","article-title":"Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton\u2019s Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies","volume":"67","author":"Robbins","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"4463","DOI":"10.1182\/blood-2023-179872","article-title":"A First-in-Human Phase 1 Trial of NX-2127, a First-in-Class Bruton\u2019s Tyrosine Kinase (BTK) Dual-Targeted Protein Degrader with Immunomodulatory Activity, in Patients with Relapsed\/Refractory B Cell Malignancies","volume":"142","author":"Danilov","year":"2023","journal-title":"Blood"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Searle, E. (2023). Initial Findings from a First-in-Human Phase 1a\/b Trial of NX-5948, a Selective Bruton\u2019s Tyrosine Kinase (BTK) Degrader, in Patients with Relapsed\/Refractory B Cell Malignancies, American Society of Hematology.","DOI":"10.1182\/blood-2023-179508"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4401","DOI":"10.1182\/blood-2023-180109","article-title":"First Results from a Phase 1, First-in-Human Study of the Bruton\u2019s Tyrosine Kinase (BTK) Degrader Bgb-16673 in Patients (Pts) with Relapsed or Refractory (R\/R) B-Cell Malignancies (BGB-16673-101)","volume":"142","author":"Seymour","year":"2023","journal-title":"Blood"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1038\/s41375-024-02317-4","article-title":"Mutation in Bruton Tyrosine Kinase (BTK) A428D Confers Resistance To BTK-Degrader Therapy in Chronic Lymphocytic Leukemia","volume":"38","author":"Wong","year":"2024","journal-title":"Leukemia"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/20\/3434\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:10:12Z","timestamp":1760112612000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/20\/3434"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,10]]},"references-count":84,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["cancers16203434"],"URL":"https:\/\/doi.org\/10.3390\/cancers16203434","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,10]]}}}