From: NF-κB signaling and its relevance to the treatment of mantle cell lymphoma
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] |