The Bruton tyrosine kinase inhibitor CC-292 shows activity in mantle cell lymphoma and synergizes with lenalidomide and NIK inhibitors depending on nuclear factor-κB mutational status

Vidal-Crespo, Anna; Rodríguez, Vanina; Matas-Céspedes, Alba; Lee, Eriong; Rivas‐Delgado, Alfredo; Giné, Eva; Navarro, Alba; Beà, Sı́lvia; Campo, Elı́as; López‐Guillermo, Armando; López‐Guerra, Mònica; Roué, Gaël; Colomer, Dolors; Pérez-Galán, Patricia

doi:10.3324/haematol.2017.168930

Cited by 18 publications

(16 citation statements)

References 14 publications

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“…In contrast, the in vitro cytotoxic effect of CC‐292, albeit significant, was modest and lower than that of ibrutinib. Similarly, a cytostatic effect of CC‐292 with a marginal pro‐apoptotic effect was previously reported in myeloma cells and mantle cell lymphoma cells . Altogether, our observations suggest that similarly to the effect of ibrutinib, inhibition of cell proliferation, rather than apoptosis induction, is one of the primary mechanisms of CC‐292 antitumor effect against CLL leukemic cells.…”

Section: Discussionsupporting

confidence: 85%

Selective BTK inhibition improves bendamustine therapy response and normalizes immune effector functions in chronic lymphocytic leukemia

Lee-Vergés

Hanna

Yazdanparast

et al. 2019

Intl Journal of Cancer

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The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been shown to be highly effective in patients with chronic lymphocytic leukemia (CLL) and is approved for CLL treatment. Unfortunately, resistance and intolerance to ibrutinib has been observed in several studies, opening the door for more specific BTK inhibitors. CC‐292 (spebrutinib) is a BTK inhibitor with increased specificity for BTK and less inhibition of other kinases. Our in vitro studies showed that CC‐292 potently inhibited B‐cell receptor signaling, activation, proliferation and chemotaxis of CLL cells. In in vivo studies using the adoptive transfer TCL1 mouse model of CLL, CC‐292 reduced tumor load and normalized tumor‐associated expansion of T cells and monocytes, while not affecting T cell function. Importantly, the combination of CC‐292 and bendamustine impaired CLL cell proliferation in vivo and enhanced the control of CLL progression. Our results demonstrate that CC‐292 is a specific BTK inhibitor with promising performance in combination with bendamustine in CLL. Further clinical trials are warranted to investigate the therapeutic efficacy of this combination regimen.

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Section: Discussionsupporting

confidence: 85%

Selective BTK inhibition improves bendamustine therapy response and normalizes immune effector functions in chronic lymphocytic leukemia

Lee-Vergés

Hanna

Yazdanparast

et al. 2019

Intl Journal of Cancer

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“…(JEKO1, and VL51). IRF4 down-regulation has been shown only in MCL cell lines sensitive to BTK inhibition with both first and second generation compounds (Thompson et al, 2017;Vidal-Crespo et al, 2017). Here, ibrutinib, acalabrutinib and spebrutinib induced a reduction of IRF4 only in the cell line sensitive to all the compounds and not in the cell line sensitive only to ibrutinib and resistant to second generation inhibitors.…”

Section: Discussionmentioning

confidence: 81%

“…In agreement with what was recently reported with zanubrutinib (Tarantelli et al , ), another second generation BTK inhibitor, acalabrutinib was much less active than the first generation BTK inhibitor ibrutinib in two cell lines (JEKO1, and VL51). IRF4 down‐regulation has been shown only in MCL cell lines sensitive to BTK inhibition with both first and second generation compounds (Thompson et al , ; Vidal‐Crespo et al , ). Here, ibrutinib, acalabrutinib and spebrutinib induced a reduction of IRF4 only in the cell line sensitive to all the compounds and not in the cell line sensitive only to ibrutinib and resistant to second generation inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Single and combined BTK and PI3Kδ inhibition with acalabrutinib and ACP‐319 in pre‐clinical models of aggressive lymphomas

et al. 2019

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Summary The B‐cell receptor and the phosphatidylinositol 3‐kinase (PI3K) signalling pathways, together with their downstream partners, represent important therapeutic targets for B‐cell lymphomas. Here, we evaluated the activity of acalabrutinib (ACP‐196) and ACP‐319 (AMG‐319), second generation inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ inhibitor, respectively, in lymphoma pre‐clinical models. The two compounds showed activity in activated B‐cell‐like diffuse large B‐cell lymphoma (ABC DLBCL), mantle cell lymphoma and marginal zone lymphoma. Two in vivo experiments with ABC DLBCL and MCL xenografts confirmed the effect of the single agents. Benefit was achieved by exposing the lymphoma cell lines to both acalabrutinib and ACP‐319. Two cell lines presented a discordant response to first and second generation BTK inhibitors, probably due to the inhibition by ibrutinib of kinases other than BTK. In conclusion, our data sustain the on‐going current trials with acalabrutinib and ACP‐319 as single agents and provide the basis for the investigation of their combination as well.

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“…Other combination therapies that target both canonical and non-canonical pathways have also been effective in inhibiting MCL cell growth and proliferation (Table 2 ). For instance, the combination of CC-292 with NIK inhibitors, AM-0216 and AM-0561, in Z138 and MAVER-1, cell lines resistant to CC-292 and ibrutinib, resulted in a significant decrease in p52 levels, via inhibition of the non-canonical pathway, and a complete lack of IκB phosphorylation, indicating total inhibition of the NF- κ B pathway [ 53 ]. This combination was also effective in primary MCL cells with BIRC3 inactivation and is a promising therapeutic choice for further investigation in vivo and in the clinical setting [ 53 ].…”

Section: Main Textmentioning

confidence: 99%

NF-κB signaling and its relevance to the treatment of mantle cell lymphoma

et al. 2018

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Mantle cell lymphoma is an aggressive subtype of non-Hodgkin B cell lymphoma that is characterized by a poor prognosis determined by Ki67 and Mantle Cell International Prognostic Index scores, but it is becoming increasingly treatable. The majority of patients, especially if young, achieve a progression-free survival of at least 5 years. Mantle cell lymphoma can initially be treated with an anti-CD20 antibody in combination with a chemotherapy backbone, such as VR-CAP (the anti-CD20 monoclonal antibody rituximab administered with cyclophosphamide, doxorubicin, and prednisone) or R-CHOP (the anti-CD20 monoclonal antibody rituximab administered with cyclophosphamide, doxorubicin, vincristine, and prednisone). While initial treatment can facilitate recovery and complete remission in a few patients, many patients experience relapsed or refractory mantle cell lymphoma within 2 to 3 years after initial treatment. Targeted agents such as ibrutinib, an inhibitor of Bruton’s tyrosine kinase, which has been approved only in the relapsed setting, can be used to treat patients with relapsed or refractory mantle cell lymphoma. However, mantle cell lymphoma cells often acquire resistance to such targeted agents and continue to survive by activating alternate signaling pathways such as the PI3K-Akt pathway or the NF-κB pathways.NF-κB is a transcription factor family that regulates the growth and survival of B cells; mantle cell lymphoma cells depend on NF-κB signaling for continued growth and proliferation. The NF-κB signaling pathways are categorized into canonical and non-canonical types, wherein the canonical pathway prompts inflammatory responses, immune regulation, and cell proliferation, while the non-canonical leads to B cell maturation and lymphoid organogenesis. Since these pathways upregulate survival genes and tumor-promoting cytokines, they can be activated to overcome the inhibitory effects of targeted agents, thereby having profound effects on tumorigenesis. The NF-κB pathways are also highly targetable in that they are interconnected with numerous other pathways, including B cell receptor signaling, PI3K/Akt/mTOR signaling, and toll-like receptor signaling pathways. Additionally, elements of the non-canonical NF- κB pathway, such as NF-κB-inducing kinase, can be targeted to overcome resistance to targeting of the canonical NF- κB pathway.Targeting the molecular mechanisms of the NF-κB pathways can facilitate the development of novel agents to treat malignancies and overcome drug resistance in patients with relapsed or refractory mantle cell lymphoma.

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The Bruton tyrosine kinase inhibitor CC-292 shows activity in mantle cell lymphoma and synergizes with lenalidomide and NIK inhibitors depending on nuclear factor-κB mutational status

Cited by 18 publications

References 14 publications

Selective BTK inhibition improves bendamustine therapy response and normalizes immune effector functions in chronic lymphocytic leukemia

Selective BTK inhibition improves bendamustine therapy response and normalizes immune effector functions in chronic lymphocytic leukemia

Single and combined BTK and PI3Kδ inhibition with acalabrutinib and ACP‐319 in pre‐clinical models of aggressive lymphomas

NF-κB signaling and its relevance to the treatment of mantle cell lymphoma

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