Preclinical models of Waldenström's macroglobulinemia and drug resistance

Ailawadhi, Sikander; Paulus, Aneel; Chanan‐Khan, Asher

doi:10.1016/j.beha.2016.08.017

Cited by 4 publications

(3 citation statements)

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“…relapse/refractory vs untreated). 33, 34 Observing that concurrent BTK and AKT inhibition could result in potentially more programmed cell death, we treated BCWM.1 and RPCI-WM1 (and their respective ibrutinib-resistant derivatives) with different concentrations of MK2206, ibrutinib or MK2206+ibrutinib for 48 h and assessed the viability. As expected, the combination of both drugs reduced WT and ibrutinib-resistant cell viability significantly more so than either ibrutinib or MK2206 alone (Figure 4b).…”

Section: Resultsmentioning

confidence: 99%

Waldenstrom macroglobulinemia cells devoid of BTKC481S or CXCR4WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment

et al. 2017

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Although ibrutinib is highly effective in Waldenstrom macroglobulinemia (WM), no complete remissions in WM patients treated with ibrutinib have been reported to date. Moreover, ibrutinib-resistant disease is being steadily reported and is associated with dismal clinical outcome (overall survival of 2.9–3.1 months). To understand mechanisms of ibrutinib resistance in WM, we established ibrutinib-resistant in vitro models using validated WM cell lines. Characterization of these models revealed the absence of BTKC481S and CXCR4WHIM-like mutations. BTK-mediated signaling was found to be highly attenuated accompanied by a shift in PI3K/AKT and apoptosis regulation-associated genes/proteins. Cytotoxicity studies using the AKT inhibitor, MK2206±ibrutinib, and the Bcl-2-specific inhibitor, venetoclax±ibrutinib, demonstrated synergistic loss of cell viability when either MK22016 or venetoclax were used in combination with ibrutinib. Our findings demonstrate that induction of ibrutinib resistance in WM cells can arise independent of BTKC481S and CXCR4WHIM-like mutations and sustained pressure from ibrutinib appears to activate compensatory AKT signaling as well as reshuffling of Bcl-2 family proteins for maintenance of cell survival. Combination treatment demonstrated greater (and synergistic) antitumor effect and provides rationale for development of therapeutic strategies encompassing venetoclax+ibrutinib or PI3K/AKT inhibitors+ibrutinib in ibrutinib-resistant WM.

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Section: Resultsmentioning

confidence: 99%

Waldenstrom macroglobulinemia cells devoid of BTKC481S or CXCR4WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment

et al. 2017

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“…To determine whether in vitro WM cell death, induced by Dara, can be recapitulated in an in vivo setting, we used our previously reported WM xenograft mouse model (Chitta et al , , ; Ailawadhi et al , ; Paulus et al , ). This model relies on implantation of RPCI‐WM1 cells, which were developed from a patient with highly drug‐resistant terminal‐stage WM, into immunocompromised mice (Drexler et al , ; Ailawadhi et al , ). Thus, we xenografted luciferase‐labelled RPCI‐WM1 cells into mice and began drug treatment on day 10 (when tumour growth was detected by bioluminescent signal intensity); mice were randomized to receive either vehicle, healthy donor PBMCs (containing natural killer and T cells) or Dara + PBMCs.…”

Section: Resultsmentioning

confidence: 99%

Targeting CD38 with daratumumab is lethal to Waldenström macroglobulinaemia cells

et al. 2018

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CD38 is expressed on Waldenström macroglobulinaemia (WM) cells, but its role as a therapeutic target remains undefined. With recent approval of the anti-CD38 monoclonal antibody, daratumumab (Dara), we hypothesized that blocking CD38 would be lethal to WM cells. In vitro Dara treatment of WM cells (including ibrutinib-resistant lines) elicited antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cell phagocytosis (ADCP) and direct apoptosis. In vivo, Dara treatment was well tolerated and delayed tumour growth in RPCI-WM1-xenografted mice. CD38 is reported to augment B-cell receptor (BCR) signalling; we noted that Dara significantly attenuated phosphorylated SYK, LYN, BTK, PLCγ2, ERK1/2, AKT, mTOR, and S6 levels, and this effect was augmented by cotreatment with ibrutinib. Indeed, WM cells, including ibrutinib-resistant WM cell lines treated with the ibrutinib + Dara combination, showed significantly more cell death through ADCC, CDC, ADCP and apoptosis relative to single-agent Dara or ibrutinib. In summary, we are the first to report the in vitro and in vivo anti-WM activity of Dara. Furthermore, we show a close connection between BCR and CD38 signalling, which can be co-targeted with ibrutinib + Dara to induce marked WM cell death, irrespective of acquired resistance to ibrutinib.

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“…Mechanisms of resistance to proteasome inhibitors in LPL/WM are poorly known. However, research in cell lines and in in vivo mouse models have demonstrated that proteasome inhibitor resistance may depend on rewiring of the proteasome machinery, by upregulating deubiquitinating enzymes (42), by BCL2 overexpression (42)(43)(44) or interaction with phorbol-12myristate-13-acetate-induced protein 1 (PMAIP1; NOXA) (45) or by epigenetic deregulation of the TP63 and CCAAT/enhancer binding protein (CEBPA) signaling (46). Further research is needed to explore in depth the mechanisms of resistance to PIs in LPL/WM.…”

Section: Proteasome Inhibitorsmentioning

confidence: 99%

Determinants of Drug Resistance in B-Cell Non-Hodgkin Lymphomas: The Case of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia

et al. 2022

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Lymphoplasmacytic lymphoma (LPL) is a rare subtype of B cell-derived non-Hodgkin lymphoma characterized by the abnormal growth of transformed clonal lymphoplasmacytes and plasma cells. This tumor almost always displays the capability of secreting large amounts of monoclonal immunoglobulins (Ig) of the M class (Waldenström Macroglobulinemia, WM). The clinical manifestations of WM/LPL may range from an asymptomatic condition to a lymphoma-type disease or may be dominated by IgM paraprotein-related symptoms. Despite the substantial progresses achieved over the last years in the therapy of LPL/WM, this lymphoma is still almost invariably incurable and exhibits a propensity towards development of refractoriness to therapy. Patients who have progressive disease are often of difficult clinical management and novel effective treatments are eagerly awaited. In this review, we will describe the essential clinical and pathobiological features of LPL/WM. We will also analyze some key aspects about the current knowledge on the mechanisms of drug resistance in this disease, by concisely focusing on conventional drugs, monoclonal antibodies and novel agents, chiefly Bruton’s Tyrosine Kinase (BTK) inhibitors. The implications of molecular lesions as predictors of response or as a warning for the development of therapy resistance will be highlighted.

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Preclinical models of Waldenström's macroglobulinemia and drug resistance

Cited by 4 publications

References 55 publications

Waldenstrom macroglobulinemia cells devoid of BTKC481S or CXCR4WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment

Waldenstrom macroglobulinemia cells devoid of BTKC481S or CXCR4WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment

Targeting CD38 with daratumumab is lethal to Waldenström macroglobulinaemia cells

Determinants of Drug Resistance in B-Cell Non-Hodgkin Lymphomas: The Case of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia

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