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] |