Issues
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Cover Image
Cover Image
MYC upregulation drives oncogenic gene expression and increased RNA synthesis in cancer cells. Meena and colleagues found that MYC-induced transcriptional hyperactivation is also associated with enhanced RNA decay, which results in accumulation of RNA catabolites and reactive oxygen species and leads to oncogenic stress and cancer cell death. This increase in RNA decay is mediated by DIS3L, the catalytic subunit of the cytoplasmic exosome, and tumor-associated mutations in DIS3L overcome RNA decay–induced stress and inhibit cell death. Compensatory purine salvage via hypoxanthine phosphoribosyltransferase 1 (HPRT1) also alleviates MYC-driven ribonucleotide catabolism, whereas HPRT1 inhibitors augment MYC-driven stress and diminish tumor progression. These findings suggest that enhancing aberrant RNA decay may represent a therapeutic strategy for MYC-driven tumors. For more information, see the article by Meena and colleagues on page 1699. Artwork by Bianca Dunn. - PDF Icon PDF LinkTable of Contents
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In This Issue
In the Spotlight
Commentary
Research Briefs
Efficacy of the Allosteric MEK Inhibitor Trametinib in Relapsed and Refractory Juvenile Myelomonocytic Leukemia: a Report from the Children’s Oncology Group
An open-label phase II trial of the MEK inhibitor trametinib in relapsed or refractory JMML resulted in an objective response rate of 50%, with 70% of patients either bridging to hematopoietic stem cell transplantation or continuing treatment following study completion.
A Next-Generation BRAF Inhibitor Overcomes Resistance to BRAF Inhibition in Patients with BRAF-Mutant Cancers Using Pharmacokinetics-Informed Dose Escalation
A phase I trial with an alternative, pharmacokinetics-informed dose escalation design demonstrated that a brain-penetrant, selective, pan-mutant BRAF inhibitor could overcome resistance to approved BRAF inhibitors in BRAF-mutant cancers.
A Functional Survey of the Regulatory Landscape of Estrogen Receptor–Positive Breast Cancer Evolution
Integration of epigenetic perturbations of cis-regulatory elements and their genetic profiling in matched relapsed patient cohort revealed the contribution of the noncoding genome to breast cancer evolution and dormancy escape upon estrogen deprivation.
Research Articles
Preexisting Skin-Resident CD8 and γδ T-cell Circuits Mediate Immune Response in Merkel Cell Carcinoma and Predict Immunotherapy Efficacy
Resident CD8 and Vδ1 γδ T cells predict immunotherapy response in Merkel cell carcinoma, providing novel biomarkers and therapeutic targets through integrated RNA-seq and spatial-omics.
Molecular Determinants of Sensitivity to Polatuzumab Vedotin in Diffuse Large B-Cell Lymphoma
N-linked sialylation of the B cell receptor restricts the efficacy of Polatuzumab Vedotin, a drug recently approved for the treatment of diffuse large B cell lymphoma, suggesting avenues for therapeutic development.
D3S-001, a KRAS G12C Inhibitor with Rapid Target Engagement Kinetics, Overcomes Nucleotide Cycling, and Demonstrates Robust Preclinical and Clinical Activities
The new-generation GDP-bound KRAS G12C inhibitor D3S-001 overcomes nucleotide cycling with high potency and rapid target engagement kinetics, which is a meaningful and clinically relevant improvement over first-generation GDP-bound KRAS G12C inhibitors.
MYC Induces Oncogenic Stress through RNA Decay and Ribonucleotide Catabolism in Breast Cancer
MYC induces a previously uncharacterized type of oncogenic stress by increasing global RNA degradation and downstream ribonucleotide catabolism and ROS accumulation; this catabolic vulnerability can be targeted in MYC-driven cancer by inhibiting purine salvage.
Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis
Machine learning models were trained to identify mutations driving clonal hematopoiesis, demonstrating the potential of data-driven approaches to support the identification of clonal hematopoiesis cases in the clinic.
CHD2 Regulates Neuron–Glioma Interactions in Pediatric Glioma
The chromatin remodeler CHD2 regulates neuron–glioma interactions and is a potential therapeutic target for H3.1K27M diffuse midline glioma.
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