Issues
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Cover Image
Cover Image
A common feature of therapeutic resistance is the enrichment of a mesenchymal-like transcriptional state that enables tumor cells to persist throughout treatment, but identifying the critical regulators of this mesenchymal state has been challenging. To address this, Killarney and colleagues assigned an epithelial–mesenchymal transition score to nearly all solid cancer cell lines within the Cancer Dependency Map and performed linear regression analyses to identify the gene dependencies that were most associated with the mesenchymal state. This analysis highlighted PKN2, a relatively understudied kinase, as a key dependency in mesenchymal-like tumor cells that promotes the mesenchymal state through PKN2–SAV1–YAP/TAZ signaling. Genetic inhibition of PKN2 prevented the emergence of drug-tolerant persister cells in the context of oncogene-targeted therapy, thereby positioning PKN2 as a promising target to combat therapeutic resistance. For more information, see the article by Killarney and colleagues on page 595. Artwork by Bianca Dunn. - PDF Icon PDF LinkTable of Contents
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In This Issue
In the Spotlight
Review
Research Briefs
Androgen Receptor Inhibition Increases MHC Class I Expression and Improves Immune Response in Prostate Cancer
Tumor cell–intrinsic androgen receptor signaling represses antigen processing and presentation in prostate cancer but can be therapeutically modulated to improve T cell–mediated killing and tumor control.
NOTCH1 Drives Sexually Dimorphic Immune Responses in Hepatocellular Carcinoma
Sex impacts immune responses in NOTCH1-driven hepatocellular carcinomas, making females more resistant than males due to a defect in the dendritic cell–T cell axis which can be restored by CD40 agonism.
Research Articles
Ancestral Differences in Anticancer Treatment Efficacy and Their Underlying Genomic and Molecular Alterations
A systematic analysis of clinical trial data uncovers ancestral differences in clinical outcomes, providing insights to advance more precise treatments that are tailored to diverse populations.
Tracking Nongenetic Evolution from Primary to Metastatic ccRCC: TRACERx Renal
A genomic and transcriptomic analysis of patients with clear-cell renal cell carcinoma reveals clinically relevant patterns of nongenetic evolution, including progressive immune dysfunction and cGAS–STING suppression.
Temporal Genomic Analysis of Homogeneous Tumor Models Reveals Key Regulators of Immune Evasion in Melanoma
Analysis of homogeneous rejected and non-rejected melanoma tumors uncovers critical immune evasion mechanisms, identifies MIF as a key regulator, and stresses the key role of tumor-associated macrophages in immunosuppression.
Discovery of BBO-8520, a First-In-Class Direct and Covalent Dual Inhibitor of GTP-Bound (ON) and GDP-Bound (OFF) KRASG12C
BBO-8520, a dual inhibitor of KRASG12C in its GTP- and GDP-bound states, has a novel mechanism of action that enables effector blockade and optimal target coverage, even in growth factor activated states, and a phase I trial is ongoing.
PKN2 Is a Dependency of the Mesenchymal-like Cancer Cell State
Analysis of functional genomic screens reveals PKN2–TAZ signaling as one of the most specific vulnerabilities of mesenchymal-like cancer cells, whose inhibition can be used to overcome resistance to oncogene-targeted therapy.
Sympathetic Neurons Promote Small Cell Lung Cancer through the β2-Adrenergic Receptor
This study highlights the role of sympathetic innervation in small cell lung cancer, in which sympathetic nerves promote tumor growth via the ADRB2 receptor and downstream PKA signaling, thus representing a potential therapeutic target.
PIN1 Prolyl Isomerase Promotes Initiation and Progression of Bladder Cancer through the SREBP2-Mediated Cholesterol Biosynthesis Pathway
This study establishes a positive regulatory role for the PIN1 prolyl isomerase in bladder cancer, linking PIN1 and the SREBP2-mediated cholesterol biosynthesis pathway and proposing a novel strategy to inhibit bladder cancer progression.
Corrections
Correction: Targeting Translation Initiation Bypasses Signaling Crosstalk Mechanisms That Maintain High MYC Levels in Colorectal Cancer
Correction: Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways
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