Table 2.

Combination therapies targeting the NF-κB pathway

Combination therapy	Target pathway and mechanism	Tested in MCL cells/patients?
Ibrutinib with rituximab	Canonical and non-canonical NF-κB pathways; inhibits BTK; rituximab decreases phosphorylation of NIK, IκB kinase, and IκBα; diminishes IKK kinase activity; and decreases NF-κB DNA-binding activity	Yes; ongoing phase II trial at the MD Anderson Cancer Center of rituximab in combination with ibrutinib in relapsed/refractory MCL (clinicaltrials.gov)
Thalidomide with rituximab	Canonical and non-canonical NF-κB pathway; thalidomide inhibits IKK and reduces TNF-α production, along with effects of rituximab	Yes—thalidomide combined with rituximab has antitumor activity in relapsed/refractory MCL; 81% overall response rate to rituximab plus thalidomide [66]
Lenalidomide with rituximab	Canonical and non-canonical NF-κB pathway; downregulates pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6, along with effects of rituximab	Yes—overall response rate of 87% when combined with rituximab in MCL patients [67]
TGR-1202 with ibrutinib	Cross-talk between NF-κB and PI3K/Akt pathways; TGR-1202 inhibits PI3K Delta	Yes—tested in relapsed or refractory MCL and CLL patients in combination with ibrutinib in a phase 1/1b study; overall response rate of 85% in combination with ibrutinib (11/13) [52]
Perillyl alcohol (calcium blocker) with bortezomib	Cross-talk between NF-κB and TG2 signaling; inhibition of autophagy to improve sensitivity to bortezomib	Not tested in patients but tested in MCL cells; was found to suppress NF-κB signaling and improve cytotoxicity of bortezomib [51]
CC-292 with lenalidomide and NIK inhibitors, AM-0216 and AM-0561	Canonical and non-canonical NF-κB pathway; CC-292 inhibits BTK in a highly selective manner; lenalidomide downregulates pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6; NIK inhibitors inhibit alternative NF-κB signaling	Not tested in patients, but tested in MCL cell lines and primary cells; CC-292 significantly reduced BTK phosphorylation and its activity was enhanced by lenalidomide co-treatment; combination of CC-292 with NIK inhibitors had a significant cooperative effect that inhibited cell growth and induced apoptosis in Z138 and MAVER-1 [53]