Issues
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Cover Image
Resistance to targeted therapies is common and occurs through bypassing signaling pathway activation. Rationally selected combination therapy can overcome this resistance, but traditional first-in-human, phase I clinical trials are inefficient at evaluating drug combinations. In this first-in-human clinical trial, Drilon and colleagues describe a bench-to-bedside approach that combines the allosteric SHP2 inhibitor PF-07284892 (ARRY-558), which was designed to overcome bypass signaling, with inhibitors of oncogenic drivers across diverse tumor models. Patients underwent a lead-in period to characterize PF-07284892 monotherapy safety, dose-limiting toxicity, pharmacokinetics, pharmacodynamics, and efficacy prior to the introduction of one of three rational combinations to a matched targeted therapy. Patients with ALK fusion–positive lung cancer, BRAFV600E-mutant colorectal cancer, KRASG12D-mutant ovarian cancer, and ROS1 fusion–positive pancreatic cancer that had previously developed resistance to targeted therapy were treated in this manner, and combination therapy showed rapid tumor and circulating tumor DNA responses as well as durable clinical benefit. Overall, this study provides proof of concept for SHP2 inhibitors in overcoming targeted therapy resistance as well as presents a model for the accelerated testing of drug combinations in early clinical development. For more information, see the article by Drilon and colleagues on page 1789. Artwork by Bianca Dunn. - PDF Icon PDF LinkTable of Contents
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In This Issue
In the Spotlight
Review
Research Brief
SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
This phase I trial with an alternative and biologically informed dose-escalation design demonstrated targeted therapy resensitization with SHP2 inhibitor combinations in diverse oncogene-driven cancers.
Research Articles
The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study
This phase Ib study of the oral, small-molecule inhibitor of MDM2, brigimadlin (BI 907828), reveals its early activity in MDM2-amplified liposarcoma and biliary tract cancers when dosed intermittently.
Clinical Activity and Exploratory Resistance Mechanism of Milademetan, an MDM2 Inhibitor, in Intimal Sarcoma with MDM2 Amplification: An Open-Label Phase Ib/II Study
Milademetan, an MDM2 inhibitor, represents a potential therapeutic option for MDM2-amplified, wild-type TP53 intimal sarcoma, and acquired TP53 mutations detected in sequential liquid biopsies might be a novel exploratory resistance mechanism to milademetan.
Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA–Associated Pancreatic Cancer in the Clinical and Preclinical Setting
Preclinical models of germline BRCA–associated pancreatic ductal adenocarcinoma (glBRCA PDAC) that reflect different clinical time points along the response spectrum of platinum/PARP inhibitor treatment were developed and used to evaluate mechanisms of resistance to these therapies.
Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Spatial profiling of pancreatic cystic precursor lesions reveals that the transcription factor NKX6-2 drives a gastric-type transcriptional profile and indolent glandular differentiation, shedding light on intraductal papillary mucinous neoplasm pathogenesis.
Targeting N-linked Glycosylation for the Therapy of Aggressive Lymphomas
Inactivation of N-linked glycosylation of the B-cell receptor (BCR) by OST-B in diffuse large B-cell lymphoma reduces clustering, internalization, and downstream signaling of BCR, suggesting OST-B may be a potential therapeutic target in lymphoma.
Mitochondrial-Encoded Complex I Impairment Induces a Targetable Dependency on Aerobic Fermentation in Hürthle Cell Carcinoma of the Thyroid
Hürthle cell carcinoma of the thyroid is enriched in somatic mitochondrial mutations that affect complex I in the electron transport chain and impede respiration, leading to a potentially targetable reliance on aerobic fermentation for cell survival.
Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma
A CRISPR–Cas9 screen inspired by multiomic profiling of oncocytic Hürthle cell carcinoma of the thyroid revealed that loss of mitochondrial complex I induces a vulnerability to ferroptosis.
Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia
The IL3 receptor was found to exhibit different stoichiometries in acute myeloid leukemia cells, with distinct forms of receptor assembly directly driving signaling and stemness programs in leukemia stem cells.
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Metabolism
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Breast Cancer
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Drug Discovery
Cell Death
Senescence
Disease Evolution
Tumor Heterogeneity
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Microbiome
Radiotherapy
Cachexia
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Colorectal Cancer
Hepatocellular Carcinoma
Bladder Cancer
Chromosome Integrity
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