In This Issue

Jerusalem and colleagues evaluated trastuzumab deruxtecan (T-DXd) in subgroups of HER2-positive metastatic breast cancer in patients with (n = 24) and without (n = 160) a history of brain metastases (BM) from DESTINY-Breast01, confirming objective response rate and median progression-free survival were 58.3% and 18.1 months and 61.3% and 16.4 months, respectively, consistent with the primary analysis. Eight patients (47.1%) experienced a best overall intracranial response of partial or complete response, and seven patients (41.2%) had a best percentage change from baseline in brain lesion diameter consistent with stable disease. Durable clinical activity of T-DXd in patients with BMs was promising and necessitates continued investigation.

See article, p. 2754.

An understanding of the mechanisms that promote selective advantage and abnormal myeloid cell production in clonal hematopoiesis (CH) is critical in the development of therapies to reduce the risk of myeloid malignancies, cardiovascular disease, and other associated conditions. Here, using murine models, SanMiguel and colleagues find that Dnmt3a-mutant CH is promoted by tumor necrosis factor (TNFα) signaling during aging. Knockout of TNFR1 depleted the selective advantage of Dnmt3a-mutant hematopoietic stem cells, while knockout of TNFR2 caused abnormal overproduction of Dnmt3a-mutant myeloid cells. This suggests selective blockade of TNFα–TNFR1 signaling will reduce the burden of DNMT3A-mutant CH as well as progression to diseases caused by CH-mutant myeloid cells.

See article, p. 2763.

The effect of radiation therapy (RT) on tumor immunity in pancreatic ductal adenocarcinoma (PDAC) is not well understood. Lander and colleagues found that RT-induced T-cell priming was blunted in PDAC models. Stromal components were shown to cooperate and blunt RT efficacy and impair RT-induced interferon signaling. Focal adhesion kinase (FAK) inhibition rescued RT efficacy and interferon signaling in vitro and in vivo, leading to T-cell priming and enhanced long-term survival in PDAC mouse models. Analysis of PDAC tissues from a clinical trial testing FAK inhibition and RT showed evidence of stromal reprogramming and improved tumor immunity.

See article, p. 2774.

Circulating tumor DNA (ctDNA) is prevalent in children with high-risk neuroblastoma; therefore, Bosse and colleagues serially sequenced ctDNA from patients with neuroblastoma to define the clinical utility of this technology. Pathogenic and actionable variants in cancer driver genes were detected in neuroblastoma ctDNA, including alterations in ALK, ERRFI1, and several RAS–MAPK pathway and DNA damage response genes. Sequencing ctDNA also delineated dynamic tumor evolution under both ALK inhibitor and other therapeutic pressures, along with disease progression beyond that of standard disease surveillance methods. Functionally, ERRFI1 ctDNA variants associated with neuroblastoma clinical progression exhibited loss of ERRFI1's tumor-suppressive functions, supporting a direct role in tumorigenesis.

See article, p. 2800.

Dissecting tumor evolution holds promise for the discovery of new therapeutic strategies. To elucidate the evolutionary course of glioblastoma (GBM), Wu, Wu, Zhang, Zhao, and colleagues performed single-cell RNA sequencing analysis of eight multifocal GBMs and defined a transcriptomic signature associated with natural evolution (NES). Experimentally, the natural evolution transition could be initiated through hypoxia and was associated with activation of the HIF1A–FOSL2 regulatory axis. FOSL2 further regulated ANXA1 expression, leading to recruitment and polarization of bone marrow–derived macrophages and suppression of T-cell IFNγ production and proliferation. The polarized macrophages, in turn, endow tumors with an increase in NES transition and migratory capacity.

See article, p. 2820.

Genome-wide association studies have identified several common noncoding prostate cancer (PCa) germline risk alleles. Yuan and colleagues conducted integrative 3D spatial genomic analysis and report that most of these risk alleles regulate transcription via enhancer reprogramming and long-range chromatin interactions. The transcriptional effects of germline risk alleles were influenced by somatic driver mutations such as loss of PTEN or RB1. The 3D genomic approach also facilitated the fine-mapping of functional risk alleles and their target genes, while single-cell RNA sequencing revealed that the transcriptomic targets of the PCa risk alleles were enriched in multiple developmental lineages of the prostate and regulated diverse cellular processes.

See article, p. 2838.

To provide the largest whole-genome sequencing study of melanoma to date, Newell, Johansson, and colleagues analyzed 570 tumors spanning the melanoma subtypes that occur at different body site locations. Cutaneous melanomas have the highest point mutation burden, while uveal has the lowest. Both acral and mucosal melanomas have a high number of complex structural rearrangement events such as chromothripsis. Uveal melanoma is genomically distinct from other subtypes, but cutaneous, acral, and mucosal melanomas share alterations in components of the MAPK, PI3K, p53, p16, and telomere pathways. Altogether, this work provides insights into the mutational mechanisms of melanoma development.

See article, p. 2856.

Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers driven by H3K27M oncohistones, which perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. Panditharatna, Marques, and colleagues discovered that H3K27M gliomas are dependent on core components of the BAF chromatin remodeling complex to regulate enhancer and transcription factor landscapes maintaining an oncogenic progenitor state. Genetic or pharmacologic perturbation of the catalytic subunit SMARCA4 opposes proliferation, promotes differentiation, and improves overall survival in patient-derived xenograft mouse models. In summary, the translational potential of therapeutic inhibition of the BAF complex for children with H3K27M gliomas was demonstrated.

See article, p. 2880.

Diffuse midline glioma (DMG) is a devasting disease with few treatment options. Mo, Duan, Zhang, and colleagues identified SMARCA4, the catalytic subunit of mammalian SWI/SNF chromatin remodeler, as a critical dependence for H3K27M-altered DMG. Genetic or pharmacologic inhibition of SMARCA4 results in reduced fitness of H3K27M-altered DMG cells in vitro and decreased the growth of DMG xenografts in vivo. Furthermore, the transcription factor SOX10 helps recruit SMARCA4 to gene regulatory elements of genes involved in cell growth and extracellular matrix in H3.3K27M DMG cells. Together, these studies support that targeting SMARCA4 could have a therapeutic benefit for patients with H3K27M-altered DMG.

See article, p. 2906.

Determining the genetic mutations necessary to drive disease versus those that are inconsequential bystanders is necessary for precision medicine. Langille and colleagues developed a somatic CRISPR/Cas9 mutagenesis screen to identify breast cancer genes individually mutated at low frequency that cooperate with the oncogenic PIK3CA^H1047R mutation to transform mammary epithelial cells. Genes involved in epigenetic regulation, referred to as “EpiDrivers,” were indicated to be a major tumor-suppressive mechanism. PIK3CA^H1047R activation, along with concomitant EpiDriver loss, led to alveolar-like lineage conversion of basal mammary epithelial cells and accelerated luminal-like tumor formation, suggesting a role in early tumorigenesis, with 39% of human breast tumors having these EpiDriver mutations.

See article, p. 2930.