Issues
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Cover Image
Cover Image
KRAS, NRAS, and HRAS make up the RAS family of protooncogenes, which is one of the most frequently mutated families in human cancers. Recent breakthroughs in targeting KRAS have occurred with KRASG12C inhibitors, such as sotorasib or adagrasib, potently and selectively inhibiting this mutation through covalent interaction with the mutant cysteine. However, it is not known whether these inhibitors also target NRASG12C or HRASG12C, which have high amino acid sequence similarity. In this study, Rubinson, Tanaka, and colleagues tested the ability of available KRASG12C inhibitors to target NRASG12C or HRASG12C and showed that, although sotorasib can target both NRASG12C and HRASG12C, it has 5-fold greater potency against NRASG12C than the other RAS isoforms due to the amino acid at position 95. Moreover, treatment with sotorasib led to a dramatic reduction in tumor size in a patient with NRASG12C-mutant colorectal cancer, providing clinical proof-of-concept for these findings. For more information, see the article by Rubinson, Tanaka, and colleagues on page 727. Artwork by Bianca Dunn. - PDF Icon PDF LinkTable of Contents
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In This Issue
In the Spotlight
In Focus
Review
Research Briefs
Sotorasib Is a Pan-RASG12C Inhibitor Capable of Driving Clinical Response in NRASG12C Cancers
Sotorasib and other selected KRASG12C inhibitors leverage differential dependence on switch-II pocket binding at amino acid position 95 to target all RASG12C isoforms, which has critical implications for the treatment of NRASG12C- or HRASG12C-mutant tumors.
Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms
A dual-recombinase reversible knock-in/knock-out mouse model of Jak2V617F validates the absolute requirement of Jak2V617F in sustaining myeloproliferative neoplasms and provides rationale for the clinical development of mutant-selective JAK2V617F inhibitors.
TREX1 Inactivation Unleashes Cancer Cell STING–Interferon Signaling and Promotes Antitumor Immunity
Preventing the feedback induction of TREX1 downstream of tumor cell STING results in robust interferon signaling and can render cancer cells vulnerable to NK and other immune cell–mediated killing, as well as immune checkpoint blockade.
Research Articles
Early Immune Remodeling Steers Clinical Response to First-Line Chemoimmunotherapy in Advanced Gastric Cancer
A phase II sequential chemoimmunotherapy trial in frontline stomach cancer demonstrates the importance of early tumor microenvironment remodeling to inform patients who benefit from adding the anti–PD-1 inhibitor pembrolizumab.
Pan-Cancer Comparative and Integrative Analyses of Driver Alterations Using Japanese and International Genomic Databases
A multi-cohort, pan-cancer analysis uncovered racial disparities in cancer genomes between Asian and White populations and elucidated pairwise relationships of driver alterations, providing valuable resources for precision medicine in cancer.
Acquired Cross-Resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC Paralogs
A large panel of patient-derived xenograft models of small cell lung cancer reveal that extrachromosomal amplifications of MYC family genes arise after relapse to drive cross-resistance to multiple chemotherapeutic regimens.
Co-clinical Trial of Novel Bispecific Anti-HER2 Antibody Zanidatamab in Patient-Derived Xenografts
Patient-derived xenografts from pre- and post-treatment biopsies reflect the antitumor activity seen with HER2 antibody zanidatamab in a clinical trial and highlight MET amplification as a mechanism of acquired resistance.
Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations
A screen of 109 anticancer drugs in 755 pan-cancer cell lines, accompanied by a prioritization framework, was conducted, and three examples of high-priority hits that offered a combination benefit were described and confirmed both in vitro and in vivo.
Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells
Epigenetic reprogramming underlies dormancy after endocrine treatment in estrogen receptor–positive breast cancer, and targeting the epigenome during this adaptation has potential clinical implications.
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