CXCR4
          S338X clonality is an important determinant of ibrutinib outcomes in patients with Waldenström macroglobulinemia

Gustine, Joshua; Liu, Xu; Tsakmaklis, Nicholas; Demos, Maria; Kofides, Amanda; Chen, Jiaji G.; Liu, Xia; Munshi, Manit; Guerrera, Maria Luisa; Chan, Gloria; Patterson, Christopher J.; Keezer, Andrew; Meid, Kirsten; Dubeau, Toni; Yang, Guang; Hunter, Zachary; Treon, Steven P.; Castillo, Jorge J.

doi:10.1182/bloodadvances.2019000635

Cited by 28 publications

(24 citation statements)

References 23 publications

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“…Du et al showed that CXCR4 is a valuable prognostic marker in AML, in addition to age, leukocytosis, Fetal Liver Tyrosine Kinase 3 (FLT3) mutant, and extramedullary infiltration. High CXCR4 expression is also an independent risk factor for total survival time in patients with AML [114]. Finally, in multiple myeloma (MM) cells, CXCR4 expression correlated with disease progression [115], chemotherapy resistant MRD [116], and poor prognosis [117], while an increase in the CXCL12 serum expression level was associated with increased osteolytic disease and increased BM angiogenesis [118].…”

Section: Cxcl12/cxcr4 Axis In Hematological Tumors: a Crucial Hub Formentioning

confidence: 99%

“…The mutated CXCR4 receptor continues to generate pro-survival signals upon CXCL12 stimulation. The CXCR4 S338X clonality of ≥ 25% represents a potential biomarker for inferior responses to ibrutinib therapy [114]. Responses to ibrutinib and survival are not only impacted by MYD88 L265P but also by CXCR4 mutations [100].…”

Section: Waldenstrom's Macroglobulinemiamentioning

confidence: 99%

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New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

et al. 2020

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Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and spread. At present, different cancer types have been shown to overexpress C-X-C chemokine receptor type 4 (CXCR4) and to respond to its ligand C-X-C motif chemokine 12 (CXCL12). The CXCL12/CXCR4 axis influences cancer biology, promoting survival, proliferation, and angiogenesis, and plays a pivotal role in directing migration of cancer cells to sites of metastases, making it a prognostic marker and a therapeutic target. More recently, mutations in the C-terminus of CXCR4 have been identified in the genomic landscape of patients affected by Waldenstrom’s macroglobulinemia, a rare B cell neoplasm. These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. In this review, we summarize the current knowledge on the relevance of CXCR4 mutations in cancer biology, focusing on its importance as predictors of clinical presentation and response to therapy.

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Section: Cxcl12/cxcr4 Axis In Hematological Tumors: a Crucial Hub Formentioning

confidence: 99%

Section: Waldenstrom's Macroglobulinemiamentioning

confidence: 99%

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

et al. 2020

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“…In contrast, WM patients with wild-type MYD88 wt usually harbor activating mutations of the NFkappaB pathway downstream of BTK, which is associated with ibrutinib resistance. Approximately one third of WM patients with MYD88 L265P develop subclonal mutations of the chemokine receptor CXCR4 S338X that promote PI3K-AKT and ERK cascades, which are responsible for the acquired ibrutinib resistance (Figure 7) [133,134].…”

Section: Resistance To Ibrutinib and Other Bruton Tyrosine-kinase Inhmentioning

confidence: 99%

Drug Resistance in Non-Hodgkin Lymphomas

Klener

Klánová

2020

IJMS

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Non-Hodgkin lymphomas (NHL) are lymphoid tumors that arise by a complex process of malignant transformation of mature lymphocytes during various stages of differentiation. The WHO classification of NHL recognizes more than 90 nosological units with peculiar pathophysiology and prognosis. Since the end of the 20th century, our increasing knowledge of the molecular biology of lymphoma subtypes led to the identification of novel druggable targets and subsequent testing and clinical approval of novel anti-lymphoma agents, which translated into significant improvement of patients’ outcome. Despite immense progress, our effort to control or even eradicate malignant lymphoma clones has been frequently hampered by the development of drug resistance with ensuing unmet medical need to cope with relapsed or treatment-refractory disease. A better understanding of the molecular mechanisms that underlie inherent or acquired drug resistance might lead to the design of more effective front-line treatment algorithms based on reliable predictive markers or personalized salvage therapy, tailored to overcome resistant clones, by targeting weak spots of lymphoma cells resistant to previous line(s) of therapy. This review focuses on the history and recent advances in our understanding of molecular mechanisms of resistance to genotoxic and targeted agents used in clinical practice for the therapy of NHL.

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“…With 13 patients the majority expressed CXCR4 S338X C > G only and when analyzed in relation to MYD88 L265P showed a clonal distribution of 44.5%. For 7 WM patients who expressed both CXCR4 S338X mutations (C > G and C > A), the fraction of cells expressing CXCR4 S338X relative to MYD88 L265P was around 4% [ 72 , 73 ]. In contrast to data on CXCR4 mutations data on the expression levels of CXCR4 are scarce in WM compared to normal counterparts.…”

Section: Waldenström’s Macroglobulinemia—a Scylla Like Heterogenous Lmentioning

confidence: 99%

“…As seen in relapsed patients responses were depending on the mutational status with a drop in major (94% v 71%) and very good partial (31 v 7%) responses for patients with mutated CXCR4 and delayed time to major responses in this patient group (1.8 v 7.3 months; P = 0.01) [ 64 ]. Responses to Ibrutinib and also PFS depends also on the allelic burden of CXCR4 as was shown in a smaller retrospective analysis of 37 patients treated with ibrutinib: in patients with CXCR4 S338X mutations, clonality of ≥25% was associated with lower response rates and inferior PFS compared to patients with <25% clonality [ 72 ]. Based on the observation, that ibrutinib single agent has less activities in CXCR4 mutated patients and in patients with non-mutated MYD88 and CXCR4, a large international prospective study performed on behalf of the European Consortium for Waldenström’s Macroglobulinemia (ECWM) was initiated, randomizing 150 patients with treatment naive or pretreated WM between ibrutinib plus rituximab or placebo plus rituximab.…”

Section: Waldenström’s Macroglobulinemia—a Scylla Like Heterogenous Lmentioning

confidence: 99%

CXCR4 in Waldenström’s Macroglobulinema: chances and challenges

et al. 2020

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It is one of the major aims in cancer research to improve our understanding of the underlying mechanisms which initiate and maintain tumor growth and to translate these findings into novel clinical diagnostic and therapeutic concepts with the ultimate goal to improve patient care. One of the greater success stories in this respect has been Waldenström’s Macroglobulinemia (WM), which is an incurable B-cell neoplasm characterized by serum monoclonal immunoglobulin M (IgM) and clonal lymphoplasmacytic cells infiltrating the bone marrow. Recent years have succeeded to describe the molecular landscape of WM in detail, highlighting two recurrently mutated genes, the MYD88 and the CXCR4 genes: MYD88 with an almost constant and recurrent point mutation present in over 90% of patients and CXCR4 with over 40 different mutations in the coding region affecting up to 40% of patients. Intriguingly, both mutations are activating mutations leading in the case of CXCR4 to an indelible activation and perpetual signaling of the chemokine receptor. These data have shed light on the essential role of CXCR4 in this disease and have paved the way to use these findings for predicting treatment response to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and novel therapeutic approaches in WM, which might be transferable to other related CXCR4 positive diseases. Well known for its central role in cancer progression and distribution, CXCR4 is highlighted in this review with regard to its biology, prognostic and predictive relevance and therapeutic implications in WM.

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CXCR4 S338X clonality is an important determinant of ibrutinib outcomes in patients with Waldenström macroglobulinemia

Abstract: Key Points CXCR4 S338X clonality ≥25% is associated with lower very good partial response and shorter progression-free survival to ibrutinib. CXCR4 S338X clonality assessment represents a novel biomarker to predict outcomes to ibrutinib in Waldenström macroglobulinemia patients.

Cited by 28 publications

References 23 publications

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

Drug Resistance in Non-Hodgkin Lymphomas

CXCR4 in Waldenström’s Macroglobulinema: chances and challenges

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