Issues
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Cover Image
Cover Image
Resistance to the KRASG12C inhibitor adagrasib in patients with KRASG12C-mutant colorectal cancer (CRC) occurs via EGFR-mediated activation of the MAPK pathway, suggesting that adagrasib combined with an anti-EGFR antibody could be effective. Yaeger, Uboha, and colleagues evaluated dual blockade of KRASG12C and EGFR using adagrasib and cetuximab in 94 patients with previously treated KRASG12C-mutant unresectable or advanced CRC from the phase I/II KRYSTAL-1 trial. The combination was well-tolerated with promising clinical activity, and additional exploratory analyses indicated that circulating tumor DNA could aid in the identification of features related to response and acquired resistance. Together, these results suggest that the combination of adagrasib plus cetuximab could be a potential new standard of care for patients with KRASG12C-mutant CRC. For more information, see the article by Yaeger, Uboha, and colleagues on page 982. Artwork by Bianca Dunn. - PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
In This Issue
In the Spotlight
In Focus
Review
Cancer Hallmarks Review
Research Briefs
Origins of Second Malignancies in Children and Mutational Footprint of Chemotherapy in Normal Tissues
Whole genome and ultra-deep duplex sequencing uncover three different origins of second tumors in children: therapy-related, common, or independent embryologic origin, as well as the mutational impact of chemotherapies in healthy tissues.
Overcoming Clinical Resistance to EZH2 Inhibition Using Rational Epigenetic Combination Therapy
Genetic mutations that promote resistance to the EZH2 inhibitor tazemetostat in SMARCB1-deficient epithelioid sarcomas and rhabdoid tumors were identified, and a combination therapy approach to counteract this resistance was proposed, potentially guiding future clinical trials.
Research Articles
Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer
Dual KRASG12C/EGFR blockade using adagrasib plus cetuximab shows promising clinical activity and tolerable safety in heavily pretreated patients with KRASG12C-mutated unresectable or metastatic colorectal cancer from the phase I/II KRYSTAL-1 trial.
Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers
Broad-spectrum inhibition of RAS-GTP with RMC-6236 is active and tolerated at exposures that induce profound tumor regressions in preclinical models of RAS-driven cancers and that can be associated with objective responses in patients with such cancers.
Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer
Distinct microenvironment architectures and spatial cellular niches were observed in earlystage non–small cell lung cancer and were linked to tumor immunogenicity, metabolism, and clonal evolution, implicating neutrophils in poor patient outcomes.
Early Changes in Tumor-Naive Cell-Free Methylomes and Fragmentomes Predict Outcomes in Pembrolizumab-Treated Solid Tumors
Change in cell-free DNA methylomes and fragmentomes after just two cycles of pembrolizumab were associated with progression-free and overall survival in patients with various metastatic cancers, without requiring matched tumor tissue.
Deep-Learning Model for Tumor-Type Prediction Using Targeted Clinical Genomic Sequencing Data
A deep learning model trained on genomic data from routine clinical sequencing accurately classifies 38 distinct tumor types, enabling guided treatment decisions for patients with cancers of unknown or uncertain origin.
Single-Cell Chromatin Accessibility Analysis Reveals the Epigenetic Basis and Signature Transcription Factors for the Molecular Subtypes of Colorectal Cancers
A high-quality single-cell chromatin accessibility atlas of colorectal cancer epithelial cells identified two epigenetic subgroups that match intrinsic-consensus molecular subtypes along with key transcription factors and their synergistic modules that regulate subtype-specific phenotypic features.
Glioblastoma-Infiltrating CD8+ T Cells Are Predominantly a Clonally Expanded GZMK+ Effector Population
Multi-modal analysis of tumor-infiltrating lymphocytes in glioblastoma (GBM) revealed a lack of canonically exhausted CD8+ T cells and an enrichment of clonally expanded GZMK-expressing CD8+ T cells, which may have implications for immunotherapy in GBM.
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