CD40L mediated alternative NFκB-signaling induces resistance to BCR-inhibitors in patients with mantle cell lymphoma

Rauert-Wunderlich, Hilka; Rudelius, Martina; Berberich, Ingolf; Rosenwald, Andreas

doi:10.1038/s41419-017-0157-6

Cited by 22 publications

(23 citation statements)

References 40 publications

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“…Indeed, we confirmed the greater proportion of quiescent cells after 48 h, and the altered regulation of the surface antigens CD52, CD37, and CD40 and the reduced glycolytic capacity of the surviving cell population with pronounced dependence on oxidative phosphorylation after 3 d ibrutinib treatment. As these observations might arise from indirect effects, we compared the results with the effects on a resistant MCL cell line characterized by less dependence on the impaired classical NF-κB pathway by ibrutinib [ 50 , 51 ]. Thus, we could show that the detected adaptations were unique to the sensitive cell line.…”

Section: Discussionmentioning

confidence: 99%

Time-Resolved scRNA-Seq Tracks the Adaptation of a Sensitive MCL Cell Line to Ibrutinib Treatment

Fuhr

Vafadarnejad

Dietrich

et al. 2021

IJMS

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Since the approval of ibrutinib for relapsed/refractory mantle cell lymphoma (MCL), the treatment of this rare mature B-cell neoplasm has taken a great leap forward. Despite promising efficacy of the Bruton tyrosine kinase inhibitor, resistance arises inevitably and the underlying mechanisms remain to be elucidated. Here, we aimed to decipher the response of a sensitive MCL cell line treated with ibrutinib using time-resolved single-cell RNA sequencing. The analysis uncovered five subpopulations and their individual responses to the treatment. The effects on the B cell receptor pathway, cell cycle, surface antigen expression, and metabolism were revealed by the computational analysis and were validated by molecular biological methods. The observed upregulation of B cell receptor signaling, crosstalk with the microenvironment, upregulation of CD52, and metabolic reprogramming towards dependence on oxidative phosphorylation favor resistance to ibrutinib treatment. Targeting these cellular responses provide new therapy options in MCL.

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Section: Discussionmentioning

confidence: 99%

Time-Resolved scRNA-Seq Tracks the Adaptation of a Sensitive MCL Cell Line to Ibrutinib Treatment

Fuhr

Vafadarnejad

Dietrich

et al. 2021

IJMS

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“…The earliest detectable events following CD40 activation were the activation of protein tyrosine kinases, phosphoinositide-3 kinase (PI3k) and phospholipase Cg2; the activation of cAMP modulated both positive and negative CD40-induced responses (41). CD40L mediated the alternative NFκB signaling pathway in mantle cell lymphoma to induce resistance to BCR inhibitors (42). Recent studies have concentrated on the involvement of JNK/SAPK, p38 MAPK and ERK signaling pathways (4,(43)(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

Soluble CD40 ligand inhibits the growth of non‑Hodgkin's lymphoma cells through the JNK signaling pathway

Feng

Wang

2020

Oncol Lett

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The incidence of non-Hodgkin's lymphoma (NHL) has been increasing annually and has become a serious threat to human health. However, the pathogenesis of NHL remains unclear. The present study aimed to investigate the effect of soluble CD40 ligand (sCD40L) on NHL cells and its underlying mechanism. Cell Counting kit-8 assay and flow cytometry apoptosis experiments were conducted to investigate the effects of sCD40L on cell proliferation and apoptosis. Western blotting was performed to detect the protein expression levels of BAX, Bcl-2, ERK, p-ERK, JNK, p-JNK, p38, p-p38 and c-JUN. The results of the present study demonstrated that exogenous sCD40L significantly inhibited the proliferation and promoted the apoptosis of Raji and CA46 cells. Additionally, exogenous sCD40L promoted the apoptosis of lymphoma cells by activating the JNK signaling pathway.

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“…Activating the NFκB pathway also induces some degree of ibrutinib resistance. This was described mainly by genetic mechanisms as mentioned before, but the non-canonical NFκB pathway together with MAPK signaling can also be activated and thus protect the cells from ibrutinib in MCL cells by activating CD40 ( 148 , 149 ).…”

Section: Non-genetic Mechanisms Of Adaptation To Ibrutinibmentioning

confidence: 97%

Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies

Ondrisova

Mráz

2020

Front. Oncol.

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The approval of BTK and PI3K inhibitors (ibrutinib, idelalisib) represents a revolution in the therapy of B cell malignancies such as chronic lymphocytic leukemia (CLL), mantle-cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), or Waldenström’s macroglobulinemia (WM). However, these “BCR inhibitors” function by interfering with B cell pathophysiology in a more complex way than anticipated, and resistance develops through multiple mechanisms. In ibrutinib treated patients, the most commonly described resistance-mechanism is a mutation in BTK itself, which prevents the covalent binding of ibrutinib, or a mutation in PLCG2, which acts to bypass the dependency on BTK at the BCR signalosome. However, additional genetic aberrations leading to resistance are being described (such as mutations in the CARD11 , CCND1 , BIRC3, TRAF2, TRAF3, TNFAIP3, loss of chromosomal region 6q or 8p, a gain of Toll-like receptor (TLR)/MYD88 signaling or gain of 2p chromosomal region). Furthermore, relative resistance to BTK inhibitors can be caused by non-genetic adaptive mechanisms leading to compensatory pro-survival pathway activation. For instance, PI3K/mTOR/Akt, NFkB and MAPK activation, BCL2, MYC, and XPO1 upregulation or PTEN downregulation lead to B cell survival despite BTK inhibition. Resistance could also arise from activating microenvironmental pathways such as chemokine or integrin signaling via CXCR4 or VLA4 upregulation, respectively. Defining these compensatory pro-survival mechanisms can help to develop novel therapeutic combinations of BTK inhibitors with other inhibitors (such as BH3-mimetic venetoclax, XPO1 inhibitor selinexor, mTOR, or MEK inhibitors). The mechanisms of resistance to PI3K inhibitors remain relatively unclear, but some studies point to MAPK signaling upregulation via both genetic and non-genetic changes, which could be co-targeted therapeutically. Alternatively, drugs mimicking the BTK/PI3K inhibition effect can be used to prevent adhesion and/or malignant B cell migration (chemokine and integrin inhibitors) or to block the pro-proliferative T cell signals in the microenvironment (such as IL4/STAT signaling inhibitors). Here we review the genetic and non-genetic mechanisms of resistance and adaptation to the first generation of BTK and PI3K inhibitors (ibrutinib and idelalisib, respectively), and discuss possible combinatorial therapeutic strategies to overcome resistance or to increase clinical efficacy.

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CD40L mediated alternative NFκB-signaling induces resistance to BCR-inhibitors in patients with mantle cell lymphoma

Cited by 22 publications

References 40 publications

Time-Resolved scRNA-Seq Tracks the Adaptation of a Sensitive MCL Cell Line to Ibrutinib Treatment

Time-Resolved scRNA-Seq Tracks the Adaptation of a Sensitive MCL Cell Line to Ibrutinib Treatment

Soluble CD40 ligand inhibits the growth of non‑Hodgkin's lymphoma cells through the JNK signaling pathway

Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies

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