Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma

Agarwal, Rishu; Chan, Yih Chih; Tam, Constantine S.; Hunter, Tane; Vassiliadis, Dane; Teh, Charis E.; Thijssen, Rachel; Yeh, Paul; Wong, Stephen Q.; Ftouni, Sarah; Lam, Enid Y.N.; Anderson, Mary Ann; Pott, Christiane; Gilan, Omer; Bell, Charles C.; Knezevic, Kathy; Blombery, Piers; Rayeroux, Kathleen C.; Zordan, Adrian; Li, Jason; Huang, David C.S.; Wall, Meaghan; Seymour, John F.; Gray, Daniel H.D.; Roberts, Andrew W.; Dawson, Mark A.; Dawson, Sarah

doi:10.1038/s41591-018-0243-z

Cited by 156 publications

(140 citation statements)

References 57 publications

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“…Similar to CLL, IGHV mutation status and VH gene usage type is important in MCL, and mutated MCL patients have a better outcome compared to unmutated IGHV patients; however, the significance of IGHV mutation status in MCL is underestimated . Other factors with inferior outcomes include CDKN2A (locus 9p21) mutations, MYC overexpression, NOTCH1 and/or NOTCH2 mutations, NSD2 mutations ( NSD2 [ WHSC1 ] mutations are associated with an increase in H3K36 and a decrease in H3K27 methylation across the genome, thus promoting oncogenesis), CCND1 mutations, and elevated absolute monocyte count . Baculoviral IAP repeat containing three mutations ( BIRC3 ) are seen in 10%‐15% of patients with MCL .…”

Section: Advances In MCL Prognosticationmentioning

confidence: 99%

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

2019

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Unprecedented advances in our understanding of the pathobiology, prognostication, and therapeutic options in mantle cell lymphoma (MCL) have taken place in the last few years. Heterogeneity in the clinical course of MCL—indolent vs aggressive—is further delineated by a correlation with the mutational status of the variable region of immunoglobulin heavy chain, methylation status, and SOX‐11 expression. Cyclin‐D1 negative MCL, in situ MCL neoplasia, and impact of the karyotype on prognosis are distinguished. Apart from Ki‐67% and morphology pattern (classic vs blastoid/pleomorphic), the proliferation gene signature has helped to further refine prognostication. Studies focusing on mutational dynamics and clonal evolution on Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib) and/or Bcl2 antagonists (venetoclax) have further clarified the prognostic impact of somatic mutations in TP53, BIRC3, CDKN2A, MAP3K14, NOTCH2, NSD2, and SMARCA4 genes. In therapy, long‐term follow‐up on chemo‐immunotherapy studies has demonstrated durable remissions in some patients; however, long‐term toxicities, especially from second cancers, are a serious concern with chemotherapy. The therapeutic options in MCL are constantly evolving, with dramatic responses from nonchemotherapeutic agents (ibrutinib, acalabrutinib, and venetoclax). Chimeric antigen receptor therapy and combinations of nonchemotherapeutic agents are actively being studied and our focus is shifting toward making the treatment of MCL chemotherapy‐free. Still, MCL remains incurable. The following aspects of MCL continue to pose a challenge: disease transformation, role of the cytokine‐microenvironmental milieu, incorporation of positron emission tomography‐computerized tomography imaging, minimal residual disease in the prognosis, circulating tumor DNA testing for clonal evolution, predicting resistance to BTK inhibitors, and optimal management of patients who progress on BTK/Bcl2 inhibitors. Next‐generation clinical trials should incorporate nonchemotherapeutic agents and personalize the treatment based upon the genomic profile of individual patient. Recent advances in the field of MCL are reviewed.

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Section: Advances In MCL Prognosticationmentioning

confidence: 99%

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

2019

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“…Among the molecular mechanisms leading to the imbalance of the BCL-2 family, genomic analyses of patients treated with ibrutinib and venetoclax in the AIM clinical cohort have identified mutations in the SWI-SNF chromatin remodeling complex, conferring resistance to treatment in MCL. Interestingly, the authors clearly demonstrated that abnormalities in SWI-SNF, through the loss of SMARCA2 (del9p) or SMARCA4 mutations, led to downregulation of ATF3, due to the loss of accessibility of the chromatin at its locus, and therefore overexpression of BCL-X L , ATF3 being a direct BCL-X L repressor [32].…”

Section: Mechanisms Of Primary Resistancementioning

confidence: 99%

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Jullien

Gomez‐Bougie

Chiron

et al. 2020

Cells

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Apoptosis is a highly conserved mechanism enabling the removal of unwanted cells. Mitochondrial apoptosis is governed by the B-cell lymphoma (BCL-2) family, including anti-apoptotic and pro-apoptotic proteins. Apoptosis evasion by dysregulation of anti-apoptotic BCL-2 members (BCL-2, MCL-1, BCL-X L ) is a common hallmark in cancers. To divert this dysregulation into vulnerability, researchers have developed BH3 mimetics, which are small molecules that restore effective apoptosis in neoplastic cells by interfering with anti-apoptotic proteins. Among them, venetoclax is a potent and selective BCL-2 inhibitor, which has demonstrated the strongest clinical activity in mature B-cell malignancies, including chronic lymphoid leukemia, mantle-cell lymphoma, and multiple myeloma. Nevertheless, mechanisms of primary and acquired resistance have been recently described and several features such as cytogenetic abnormalities, BCL-2 family expression, and ex vivo drug testing have to be considered for predicting sensitivity to BH3 mimetics and helping in the identification of patients able to respond. The medical need to overcome resistance to BH3 mimetics supports the evaluation of innovative combination strategies. Novel agents including MCL-1 targeting BH3 mimetics are currently evaluated and may represent new therapeutic options in the field. The present review summarizes the current knowledge regarding venetoclax and other BH3 mimetics for the treatment of mature B-cell malignancies.

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“…Agarwal et al focused on the genomic profiles of MCL patients who respond or did not respond to ibrutinib and venetoclax combinatory therapy and identified a distinct genomic profile separating responders from nonresponders. Based on this very recent study, chemotherapy-resistant patients harbor 9p21.1-p24.3 locus deletion and/or mutations of the genes forming the SWI-SNF chromatin-remodeling complex (Agarwal et al, 2019). They observed that defective SWI-SNF complexes promote transcriptional upregulation of BCL-XL, which may confer resistance to the ibrutinib and venetoclax combination.…”

Section: Chemotherapy Resistance-associated Genetic Aberrations In B mentioning

confidence: 99%

Genetic alterations in B cell lymphoma subtypes as potential biomarkers for non-invasive diagnosis, prognosis, therapy, and disease monitoring

Sönmez

Küçük

2020

Turk J Biol

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Neoplastic transformation of germinal center B (GCB) cells may give rise to a variety of different B cell lymphoma subtypes, most of which show substantial heterogeneity in terms of genetic alterations and clinical features. The mutations observed in cancerrelated genes in GCB cells are related to abnormalities in the immunogenetic mechanisms associated with germinal center reaction. Recent studies have rapidly identified genomic alterations in B cell lymphomas that may be useful for better subclassification, noninvasive diagnosis, and prediction of response to therapy. The WHO recognizes different lymphoma subsets classified within 2 major categories of B cell lymphoma: Hodgkin's lymphoma (HL) and B cell non-Hodgkin's lymphoma (NHL), each with distinct genetic aberrations, including chromosomal translocations, copy number abnormalities, or point mutations. Next-generation sequencing-based technologies have allowed cancer researchers to identify somatic mutations and gene expression signatures at a rapid pace so that novel diagnostic or prognostic biomarkers, as well as therapeutic targets, can be discovered much faster than before. Indeed, deep sequencing studies have recently revealed that lymphoma-specific somatic mutations may be detected in cell-free circulating DNA obtained from the peripheral blood of B cell lymphoma patients, suggesting the possibility of minimally invasive diagnosis, monitoring, and predicting response to therapy of B cell lymphoma patients. In this study, the current status of the recurrent genetic aberrations observed during diagnosis and/ or relapse in HL and the major subtypes of B cell NHL (i.e. diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, and Burkitt lymphoma) are discussed to shed light on their potential use as noninvasive diagnostic or prognostic biomarkers and to reveal their role in lymphomagenesis as a target in therapy for newly diagnosed and chemotherapy-resistant cases.

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Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma

Cited by 156 publications

References 57 publications

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

Genetic alterations in B cell lymphoma subtypes as potential biomarkers for non-invasive diagnosis, prognosis, therapy, and disease monitoring

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