B-cell receptor / BTK signalling (to NF-κB)
The B-cell receptor is the survival switch of B cells. Signals from it pass through BTK to free NF-kappa-B, which keeps the cell alive. B-cell cancers hold it on; BTK inhibitors, proteasome inhibitors and lenalidomide each cut the line at a different point.
Overview
Antigen binding to the B-cell receptor activates SYK and BTK, then PLCγ2 and PKCβ, which assemble the CARD11-BCL10-MALT1 complex and activate the IKK kinases. IKK phosphorylates IκB, the protein that holds NF-κB (p65/p50) in the cytoplasm; IκB is ubiquitinated and destroyed by the proteasome, and NF-κB enters the nucleus to switch on BCL2, BCL-XL, IL-6, IL-10 and cyclin D. Toll-like receptors feed the same hub through MYD88 (MYD88 L265P in Waldenström macroglobulinaemia and ABC-type DLBCL), and BAFF and CD40 signals activate the alternative (NIK-dependent) branch, which matters in multiple myeloma. Activated B-cell DLBCL, chronic lymphocytic leukaemia, mantle cell lymphoma and Waldenström macroglobulinaemia depend on this circuit. Ibrutinib and the later BTK inhibitors (acalabrutinib, zanubrutinib, pirtobrutinib) block the receptor arm; bortezomib and carfilzomib stop the proteasome from destroying IκB; lenalidomide and its successors degrade IKZF1/3 and cut IRF4-driven NF-κB output in myeloma and ABC-DLBCL. Resistance comes from BTK C481S mutations, PLCγ2 mutations and CARD11 or MYD88 lesions downstream of BTK.
In one picture
A guard (IκB) holds a prisoner (NF-kappa-B) who, once free, orders the cell to survive. The B-cell receptor sends a runner (BTK) to hand the guard to the shredder (proteasome). BTK inhibitors stop the runner, proteasome inhibitors jam the shredder, and lenalidomide removes the clerks (IKZF1/3) who file the survival orders.
Diagram
top- Covalent BTK inhibitors ibrutinib, acalabrutinib, zanubrutinib; non-covalent pirtobrutinib after BTK C481S resistance; BTK degraders in trials
- Proteasome inhibitors bortezomib, carfilzomib and ixazomib block IκB degradation in multiple myeloma and mantle cell lymphoma
- Lenalidomide and the CELMoDs degrade IKZF1/3, cutting IRF4 and NF-κB output
- BCL2 inhibition (venetoclax) removes the main survival gene NF-κB switches on
Pages like this
not linked directly; found by shared links- PersonAnthony Letai
Shares Intrinsic apoptosis (BCL-2 family), BCL-2, Venetoclax, Chronic lymphocytic leukaemia.
- ProductSonrotoclax
Shares Intrinsic apoptosis (BCL-2 family), Mantle cell lymphoma, BCL-2, Venetoclax.
- TrialGLOW
Shares Ibrutinib, BCL-2, Venetoclax, Chronic lymphocytic leukaemia.
- TrialCAPTIVATE
Shares Ibrutinib, BCL-2, Venetoclax, Chronic lymphocytic leukaemia.
- PersonPaul G. Richardson
Shares Bortezomib, Lenalidomide, Multiple myeloma.
- PersonKenneth C. Anderson
Shares Bortezomib, Lenalidomide, Multiple myeloma.
- TrialCEPHEUS
Shares Bortezomib, Lenalidomide, Multiple myeloma.
- TermFixed-duration vs continuous therapy
Shares Ibrutinib, Venetoclax, Chronic lymphocytic leukaemia, Multiple myeloma.