Complex mechanisms of action of „BCR signalling“ inhibitors and development of resistance to this targeted therapy in chronic lymphocytic leukaemia
Authors:
Ľ. Košťálová 1,2; V. Šeda 1,2; M. Mráz 1,2
Authors‘ workplace:
CEITEC – Středoevropský technologický institut, Masarykova univerzita, Brno
1; Interní hematologická a onkologická klinika FN Brno a LF MU, Masarykova univerzita, Brno
2
Published in:
Transfuze Hematol. dnes,25, 2019, No. 4, p. 301-308.
Category:
Review/Educational Papers
Overview
The emergence of the BTK inhibitor ibrutinib and PI3K inhibitor idelalisib represented a revolution in the therapy of B cell malignancies. In some of these malignancies, they became the primary therapeutic strategy. However „BCR inhibitors“ function by a more complex mechanism than anticipated. The evolution of point mutations, chromosomal aberrations and changes in the physiology of malignant B cells leads to resistance in some patients treated with „BCR inhibitors“. The most commonly described aberration is the mutation in PLCγ bypassing BCR signalosome or the mutation in BTK preventing the covalent binding of ibrutinib. However, additional mutations leading to resistance are still being described. Furthermore, relative resistance to „BCR inhibitors“ can be caused by non-genetic adaptive mechanisms leading to activation of alternative pathways and „compensation“ of kinase inhibition. For instance, PI3K-Akt and NFκB activation or BCL2 upregulation lead to B cell survival even after BTK inhibition. This suggests some potentially effective therapeutic combinations of BTK/PI3K inhibitors together with other targeted inhibitors for clinical trials. Alternatively, drugs mimicking the BTK/PI3K inhibition effect can be used to prevent adhesion and migration of malignant B cells (chemokine and integrin pathway inhibition) or to block the pro-proliferative signals from the microenvironment such as IL4 (STAT inhibitors).
Keywords:
resistance – ibrutinib – idelalisib – CLL – BCR – inhibition – microenvironment
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Haematology Internal medicine Clinical oncologyArticle was published in
Transfusion and Haematology Today
2019 Issue 4
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