Pathogenetic importance and therapeutic implications of NF-κB in lymphoid malignancies

Abstract

Derangement of the nuclear factor κB (NF-κB) pathway initiates and/or sustains many types of human cancer. B-cell malignancies are particularly affected by oncogenic mutations, translocations, and copy number alterations affecting key components the NF-κB pathway, most likely owing to the pervasive role of this pathway in normal B cells. These genetic aberrations cause tumors to be 'addicted' to NF-κB, which can be exploited therapeutically. Since each subtype of lymphoid cancer utilizes different mechanisms to activate NF-κB, several different therapeutic strategies are needed to address this pathogenetic heterogeneity. Fortunately, a number of drugs that block signaling cascades leading to NF-κB are in early phase clinical trials, several of which are already showing activity in lymphoid malignancies.

Fig. 1. Compendium of CARD11 mutants in lymphoma

The coiled-coil domain of CARD11 is presented with lymphoma-derived mutants indicated. As indicated, mutants are derived from nodal DLBCL classified into the ABC or GCB subtypes (74, 83, 84), unclassified nodal and gastric DLBCL (84, 85), primary central nervous system (CNS) lymphoma (86), and follicular lymphoma (84). A ‘Δ‘ indicates a removal of amino acids, and a lower case ‘I’ followed by a number indicates insertion of amino acids.

Fig. 2. Location of recurrent MyD88 mutants present in ABC DLBCL tumors

A. The MyD88 TIR domain structure with ABC DLBCL mutants indicated. B. Space-filling model of MyD88 TIR domain illustrating that the highly recurrent L265P mutant is buried within the hydrophobic core of the domain. Also note that another recurrent mutant, M232T, is adjacent to L265 and makes Van der Wals interactions with L265.

Fig. 3. Therapeutic targets in ABC DLBCL

The pathogenesis of ABC DLBCL involves constitutive activation of BCR, MyD88 and IL-6/IL-10 signaling pathway, promoting cell survival through NF-κB, STAT3 and PI3K signaling pathways. Signaling in these pathways is induced or accentuated by recurrent mutations in ABC DLBCL that affect CD79B, MyD88, CARD11 and A20 (denoted with and asterisk). Therapeutic targets in ABC DLBCL and exemplar small molecule inhibitors include: 1. Src-family kinase (Dasatinib) (64); 2. SYK (fostamatinib/R406) (64, 201); 3. PI3Kδ (CAL-101) (64, 206, 207); 4. mTOR (rapamycin) (64); 5. BTK (PCI-32765, Dasatinib) (64); 6. PKCβ (Sotrastaurin) (64, 202); 7. MALT1 (50, 74); 8. IKKβ (MLN120B) (48, 90, 91); 9. HSP90 (geldanomycin) (195, 196); 10. IRAK4 (81); 11. NEDD8-activating enzyme (NAE) (MLN4924); JAK1 (AZD1480) (49, 81); 12. Proteasome (bortezomib) (191).