EZH2 inactivation in RAS-driven myeloid neoplasms hyperactivates RAS-signaling and increases MEK inhibitor sensitivity

Berg, Johannes Lorenz; Perfler, Bianca; Hatzl, Stefan; Uhl, Barbara; Reinisch, Andreas; Pregartner, Gudrun; Berghold, Andrea; Penz, Thomas; Schuster, Michael; Geißler, Klaus; Prokesch, Andreas; Müller‐Tidow, Carsten; Höefler, Gerald; Kashofer, Karl; Wölfler, Albert; Sill, Heinz; Caraffini, Veronica; Zebisch, Armin

doi:10.1038/s41375-021-01161-0

Cited by 4 publications

(3 citation statements)

References 17 publications

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“…Several RAS pathway inhibitors are being currently tested on clinical trials [181]. This could potentially be a suitable strategy for some ML-DS cases, as myeloid neoplasms with co-occurring mutations in EZH2 show increased dependency on RAS signalling, which renders tumour cells more sensitive to MEK inhibitors [182].…”

Section: Mutations In Ras Membersmentioning

confidence: 99%

The Mutational Landscape of Myeloid Leukaemia in Down Syndrome

Castro

Cadefau

2021

Cancers

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Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators—such as cohesin, CTCF or EZH2—and in signalling mediators of the JAK/STAT and RAS pathways. Most of them are also found in non-DS myeloid malignancies, albeit at extremely different frequencies. Intriguingly, mutations in proteins involved in the three-dimensional organization of the genome are found in nearly 50% of cases. How the resulting mutant proteins cooperate with trisomy 21 and mutant GATA1 to promote ML-DS is not fully understood. In this review, we summarize and discuss current knowledge about the sequential acquisition of genomic alterations in ML-DS.

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Section: Mutations In Ras Membersmentioning

confidence: 99%

The Mutational Landscape of Myeloid Leukaemia in Down Syndrome

Castro

Cadefau

2021

Cancers

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“…Owing to this, Lorenz Berg et al have shown that RAS-mutant myeloid leukemia cells were sensitized to MEK inhibitors upon EZH2 inactivation. Thus, co-inhibiting EZH2 and MEK might provide a novel therapeutic route for RAS-driven cancers [107]. BI-3406, a novel SOS1-KRAS interaction inhibitor designed to target the catalytic domain of SOS1, has been combined with trametinib and sensitized KRAS-driven cancers to MEK inhibition in mouse models.…”

Section: Mek Inhibitorsmentioning

confidence: 99%

Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy

Tatlı

Doğanay

2021

Molecules

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Aberrant activity of oncogenic rat sarcoma virus (RAS) protein promotes tumor growth and progression. RAS-driven cancers comprise more than 30% of all human cancers and are refractory to frontline treatment strategies. Since direct targeting of RAS has proven challenging, efforts have been centered on the exploration of inhibitors for RAS downstream effector kinases. Two major RAS downstream signaling pathways, including the Raf/MEK/Erk cascade and the phosphatidylinositol-3-kinase (PI3K) pathway, have become compelling targets for RAS-driven cancer therapy. However, the main drawback in the blockade of a single RAS effector is the multiple levels of crosstalk and compensatory mechanisms between these two pathways that contribute to drug resistance against monotherapies. A growing body of evidence reveals that the sequential or synergistic inhibition of multiple RAS effectors is a more convenient route for the efficacy of cancer therapy. Herein, we revisit the recent developments and discuss the most promising modalities targeting canonical RAS downstream effectors for the treatment of RAS-driven cancers.

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“…As an exemplar, the exceptional sensitivity to EZH2i of SMARCB1-deficient epithelial sarcomas serves as proof of concept. Conversely, an emerging example currently arises from RAS mutated and EZH2 deficient myeloid neoplasms, which become exquisitely dependent upon MEK inhibition [37]. Nonetheless, based on the current knowledge we expect a longroad for the successful introduction of EZH2i in the clinical treatment setting of myeloid neoplasms.…”

Section: Targeting Histone Tail Methylationmentioning

confidence: 99%

Next generation epigenetic modulators to target myeloid neoplasms

Sasca

Guezguez

Kühn

2021

Current Opinion in Hematology

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Purpose of review Comprehensive sequencing studies aimed at determining the genetic landscape of myeloid neoplasms have identified epigenetic regulators to be among the most commonly mutated genes. Detailed studies have also revealed a number of epigenetic vulnerabilities. The purpose of this review is to outline these vulnerabilities and to discuss the new generation of drugs that exploit them. Recent findings In addition to deoxyribonucleic acid-methylation, novel epigenetic dependencies have recently been discovered in various myeloid neoplasms and many of them can be targeted pharmacologically. These include not only chromatin writers, readers, and erasers but also chromatin movers that shift nucleosomes to allow access for transcription. Inhibitors of protein-protein interactions represent a novel promising class of drugs that allow disassembly of oncogenic multiprotein complexes. Summary An improved understanding of disease-specific epigenetic vulnerabilities has led to the development of second-generation mechanism-based epigenetic drugs against myeloid neoplasms. Many of these drugs have been introduced into clinical trials and synergistic drug combination regimens have been shown to enhance efficacy and potentially prevent drug resistance.

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EZH2 inactivation in RAS-driven myeloid neoplasms hyperactivates RAS-signaling and increases MEK inhibitor sensitivity

Cited by 4 publications

References 17 publications

The Mutational Landscape of Myeloid Leukaemia in Down Syndrome

The Mutational Landscape of Myeloid Leukaemia in Down Syndrome

Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy

Next generation epigenetic modulators to target myeloid neoplasms

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