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Table 2 Resistance mechanisms to BTK inhibitors in B cell malignancies

From: Targeting Bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies

B cell malignancy subtype Covalent BTK inhibitors Mechanisms underlying resistance
Primary resistance
MCL Ibrutinib Mutations involving NF-κB pathway: A20 mutations, TRAF2 mutations, BIRC3 mutations or BIRC2 mutations, RELA E39Q mutation, and others [76, 77]
Sustained PI3K/AKT/mTOR activation [28, 78]
Tumor microenvironment [79]
Metabolic reprogramming toward oxidative phosphorylation and glutaminolysis [80]
CCND1 mutation [81]
WM Ibrutinib CXCR4 WHIM-like mutations [82]
DLBCL Ibrutinib PIM1 mutation [83]
PI3K/AKT activation [84]
MAPK activation [84]
Aberrations activating NF-κB pathway: CARD11 mutation, A20 aberrations [85]
High expression of PDGFD [86]
Acquired resistance
CLL/SLL Ibrutinib BTK C481 and T474 mutations [24, 87, 88]
PLCG2 mutations (R665W, S707, L845F, and others) [87]
del(8p) [89]
CLL/SLL Acalabrutinib BTK C481 mutations and T474I mutation, PLCG2 mutations [29]
CLL/SLL Zanubrutinib BTK Leu528Trp mutation and C481 mutation [31]
MCL Ibrutinib BTK C481S mutation [28]
PLCG2 mutations [76]
CARD11 mutation [76]
Tumor microenvironment [79]
WM Ibrutinib BTK C481 mutations [26]
PLCG2 Tyr495His mutation [26]
MZL Ibrutinib BTK C481S mutation [90]
PLCG2 R665W [90]
DLBCL Ibrutinib BTK C481S mutation [91]
  1. BTK Bruton tyrosine kinase, MCL mantle cell lymphoma, WM Waldenstrom's macroglobulinemia, DLBCL diffuse large B cell lymphoma, CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma, MZL marginal zone lymphoma