Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127-Reference-Cited by-同舟云学术

Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127

Published:2024-02-02 Issue:6682 Volume:383 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Montoya Skye¹^ORCID,Bourcier Jessie²^ORCID,Noviski Mark³^ORCID,Lu Hao³,Thompson Meghan C.⁴^ORCID,Chirino Alexandra¹^ORCID,Jahn Jacob¹^ORCID,Sondhi Anya K.¹^ORCID,Gajewski Stefan³^ORCID,Tan Ying Siow (May)³^ORCID,Yung Stephanie³,Urban Aleksandra⁵⁶^ORCID,Wang Eric⁷,Han Cuijuan⁷^ORCID,Mi Xiaoli²^ORCID,Kim Won Jun²^ORCID,Sievers Quinlan²^ORCID,Auger Paul³^ORCID,Bousquet Hugo³,Brathaban Nivetha³,Bravo Brandon³,Gessner Melissa³,Guiducci Cristiana³,Iuliano James N.³^ORCID,Kane Tim³^ORCID,Mukerji Ratul³^ORCID,Reddy Panga Jaipal³^ORCID,Powers Janine³,Sanchez Garcia de los Rios Mateo³,Ye Jordan³^ORCID,Barrientos Risso Carla¹^ORCID,Tsai Daniel¹^ORCID,Pardo Gabriel¹,Notti Ryan Q.⁸^ORCID,Pardo Alejandro¹,Affer Maurizio¹^ORCID,Nawaratne Vindhya¹,Totiger Tulasigeri M.¹^ORCID,Pena-Velasquez Camila²,Rhodes Joanna M.⁹^ORCID,Zelenetz Andrew D.¹⁰^ORCID,Alencar Alvaro¹,Roeker Lindsey E.²^ORCID,Mehta Sanjoy¹¹^ORCID,Garippa Ralph¹¹,Linley Adam¹²^ORCID,Soni Rajesh Kumar¹³^ORCID,Skånland Sigrid S.²⁵⁶^ORCID,Brown Robert J.³^ORCID,Mato Anthony R.²,Hansen Gwenn M.³^ORCID,Abdel-Wahab Omar²^ORCID,Taylor Justin¹^ORCID

Affiliation:

1. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.

2. Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

3. Nurix Therapeutics, San Francisco, CA, USA.

4. Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

5. Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

6. K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

7. The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.

8. Laboratory of Molecular Electron Microscopy, Rockefeller University, New York, NY, USA.

9. Division of Hematology-Oncology, Department of Medicine at Zucker School of Medicine at Hofstra/Northwell, CLL Research and Treatment Center, Lake Success, NY, USA.

10. Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

11. Gene Editing and Screening Core Facility, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Institute and Cancer Center, New York, NY, USA.

12. Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.

13. Proteomics and Macromolecular Crystallography Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.

Abstract

Increasing use of covalent and noncovalent inhibitors of Bruton’s tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/science.adi5798

Reference72 articles.

1. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma

2. Targeting Bruton's tyrosine kinase in B cell malignancies

3. Targeting BTK in CLL: Beyond Ibrutinib

4. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia

5. Mechanisms of Resistance to Noncovalent Bruton’s Tyrosine Kinase Inhibitors

Cited by 2 articles. 订阅此论文施引文献订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献

1. Degradation trumps mutations in cancer;Science;2024-02-02

2. Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton’s Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies;Journal of Medicinal Chemistry;2024-02-01