Version 1
: Received: 18 July 2024 / Approved: 18 July 2024 / Online: 18 July 2024 (17:24:05 CEST)
How to cite:
Bravo-Gonzalez, A.; Alasfour, M.; Soong, D.; Noy, J.; Pongas, G. Advances in Targeted Therapy: Addressing Resistance to BTK Inhibition in B‐Cell Lymphoid Malignancies. Preprints2024, 2024071534. https://doi.org/10.20944/preprints202407.1534.v1
Bravo-Gonzalez, A.; Alasfour, M.; Soong, D.; Noy, J.; Pongas, G. Advances in Targeted Therapy: Addressing Resistance to BTK Inhibition in B‐Cell Lymphoid Malignancies. Preprints 2024, 2024071534. https://doi.org/10.20944/preprints202407.1534.v1
Bravo-Gonzalez, A.; Alasfour, M.; Soong, D.; Noy, J.; Pongas, G. Advances in Targeted Therapy: Addressing Resistance to BTK Inhibition in B‐Cell Lymphoid Malignancies. Preprints2024, 2024071534. https://doi.org/10.20944/preprints202407.1534.v1
APA Style
Bravo-Gonzalez, A., Alasfour, M., Soong, D., Noy, J., & Pongas, G. (2024). Advances in Targeted Therapy: Addressing Resistance to BTK Inhibition in B‐Cell Lymphoid Malignancies. Preprints. https://doi.org/10.20944/preprints202407.1534.v1
Chicago/Turabian Style
Bravo-Gonzalez, A., Jose Noy and Georgios Pongas. 2024 "Advances in Targeted Therapy: Addressing Resistance to BTK Inhibition in B‐Cell Lymphoid Malignancies" Preprints. https://doi.org/10.20944/preprints202407.1534.v1
Abstract
B-cell lymphoid malignancies is a heterogeneous group of hematologic cancers, where Bruton's 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 can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLCγ2) resulting in downstream signaling. To bypass the C481S mutation, non-covalent BTK inhibitors, 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 BTK inhibitors. 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 BTK inhibitors and the development of new therapeutic strategies highlight the ongoing advances, that are being made towards the pursue of cure of B-cell lymphoid malignancies.
Keywords
lymphoma; B‐cell; hematologic neoplasms; bruton tyrosine kinase; protein kinase inhibitors; drug resistance; neoplasm; ibrutinib; pirtobrutinib; molecular targeted therapy; chronic lymphocytic leukemia; hematopoietic stem cell transplantation; covalent inhibitors; protein degradation
Subject
Medicine and Pharmacology, Hematology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
