Issues
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Cover Image
Cover Image
Oncogenic dysregulation of the receptor tyrosine kinase MET is known to occur via several possible mechanisms in human tumors, including gene amplification, gene fusion, exon 14 skipping, and protein overexpression, all of which can be targeted by approved drugs or agents in clinical development. Activating point mutations in the MET tyrosine kinase domain (TKD) have also been observed in some tumors, prompting Pecci, Nakazawa, and colleagues to perform a pan-cancer analysis to determine the prevalence of these alterations. Across over 600,000 patients profiled, the prevalence of MET TKD mutations was 0.5%. The oncogenic potential of MET TKD mutants and sensitivity to MET-targeted tyrosine kinase inhibitors were characterized in vitro, and numerous MET TKD mutants were identified to be potentially actionable. Consistent with these findings, two patients with MET TKD-mutant lung adenocarcinoma enrolled in a clinical trial of the MET inhibitor elzovantinib had confirmed partial responses. The study exemplifies how comprehensive genomic tumor profiling can detect rare but targetable driver alterations and identifies an additional subgroup of patients who may benefit from MET-targeted therapies. For more information, see the article by Pecci, Nakazawa, and colleagues on page 1440. Artwork by Bianca Dunn. - PDF Icon PDF LinkTable of Contents
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In This Issue
In the Spotlight
Review
Research Articles
Lifileucel, an Autologous Tumor-Infiltrating Lymphocyte Monotherapy, in Patients with Advanced Non–Small Cell Lung Cancer Resistant to Immune Checkpoint Inhibitors
In this phase 2 trial, the tumor-infiltrating lymphocyte therapy lifileucel showed potential as a one-time treatment option for patients with metastatic non-small cell lung cancer who progressed after prior immunotherapy.
St. Jude Survivorship Portal: Sharing and Analyzing Large Clinical and Genomic Datasets from Pediatric Cancer Survivors
A free web portal shares two cohorts’ data of over 7,700 5-year childhood cancer survivors with decades of follow-up, allowing online exploration and analysis of whole-genome sequencing genetic and clinical data.
Spatially Segregated Macrophage Populations Predict Distinct Outcomes in Colon Cancer
Multiplex protein tissue profiling shows that distinct tumor-associated macrophage populations occupy spatially segregated microenvironments that predict opposite outcomes in colon cancer.
Activating Point Mutations in the MET Kinase Domain Represent a Unique Molecular Subset of Lung Cancer and Other Malignancies Targetable with MET Inhibitors
Activating MET tyrosine kinase domain mutations were detected across diverse cancer types and showed sensitivity to several MET inhibitors, suggesting that this newly characterized molecular cancer subgroup can be a targetable oncogenic driver.
Novel WRN Helicase Inhibitors Selectively Target Microsatellite-Unstable Cancer Cells
The discovery and characterization of novel WRN helicase inhibitors provides pharmacological validation for the clinical development of WRN inhibitors for the treatment of patients with MSI tumors.
BRCA1-Mediated Dual Regulation of Ferroptosis Exposes a Vulnerability to GPX4 and PARP Co-Inhibition in BRCA1-Deficient Cancers
BRCA1 deficiency renders cancer cells resistant to erastin-induced ferroptosis but makes them susceptible to GPX4 inhibitor-induced ferroptosis, offering a targetable vulnerability for BRCA1-deficient cancers through co-inhibition of GPX4 and PARP.
ZNF397 Deficiency Triggers TET2-Driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer
ZNF397 is a molecular switch between AR-driven, therapy-sensitive prostate cancer and TET2-driven, lineage plastic, therapy-resistant cancer, highlighting TET2 and epigenetic rewiring as targets to overcome resistance.
Condensate-Promoting ENL Mutation Drives Tumorigenesis In Vivo Through Dynamic Regulation of Histone Modifications and Gene Expression
Mutations in the chromatin reader ENL drive AML by altering chromatin modifications and gene expression through condensate formation, the disruption of which via mutagenesis or with a small molecule blocks leukemogenesis, revealing a novel therapeutic strategy.
Phosphocreatine Promotes Epigenetic Reprogramming to Facilitate Glioblastoma Growth Through Stabilizing BRD2
GBM stem cells produce excess phosphocreatine to drive epigenetic reprogramming and ensure accurate chromosome segregation, which highlights the potential for targeting phosphocreatine as a promising therapeutic approach for GBM.
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