Highlighted Research Articles

Rezatapopt reactivation of p53-Y220C elicits clinical responses but also selects for mechanisms of on-target resistance in patients. Fece de la Cruz, Varkaris, and colleagues profiled tumor tissue and circulating tumor DNA from two patients enrolled in the phase I/II PYNNACLE trial, revealing numerous secondary TP53 alterations that arise in cis with Y220C at progression. These fall into two classes: DNA-binding domain and truncating events that extinguish p53 transcriptional activity and mutations within the Y220C pocket that impede drug binding, with some also preserving p53 function. Functional modeling confirmed loss of target gene induction and abrogation of rezatapopt sensitivity. These findings define distinct classes of rezatapopt resistance and support the structure-guided development of next-generation mutant p53 reactivators and rational combinations.See article, p. 677.Using U.S. Cancer Statistics data from 2001 to 2022, Shiels and colleagues found that childhood cancer incidence increased nearly 1% annually until 2016 before declining at a similar rate thereafter. Lymphoma rates rose, leukemia and CNS tumor rates increased then declined, and other epithelial neoplasms generally were stable with a mid-decade increase. Geographic and age-group variations persisted, and an estimated 1,040 excess cases occurred in 2022 relative to 2001 rates. Modifications in cancer classifications, the implementation of cancer screening, and changes in diagnostic technology were likely to have contributed to these trends. These results shed light on how changes in clinical screening, diagnosis, and putative risk factors shape national childhood cancer trends and emphasize the need for ongoing surveillance.See article, p. 686.In the NUTRIVENTION trial, Shah, Cogrossi, and colleagues reported that a high-fiber, plant-based diet was feasible and well tolerated. This diet produced improvements in body mass index, insulin resistance, gut microbiome diversity, and immune-based changes in individuals with monoclonal gammopathy of undetermined significance or smoldering multiple myeloma. In parallel, findings were translated in preclinical mouse studies that demonstrated that fiber-driven short-chain fatty acid production enhanced antitumor immunity, reduced pro-inflammatory monocyte and T-cell subsets, and delayed progression to myeloma, independent of calorie restriction. Together, these findings provide support that dietary fiber is a low-risk metabolic and immunologic modulator capable of influencing disease trajectory in plasma-cell precursor states.See article, p. 697.Yuan and colleagues developed single-cell genotype-to-phenotype sequencing (scG2P), a single-cell assay that jointly profiles DNA mutations and mRNA phenotypes. In this study, scG2P was performed to map somatic clonal mosaicism in the aged human esophagus. Across cells from six individuals, large numbers of clones carried only one driver mutation, often in NOTCH1 or TP53, with rare double-mutant clones. NOTCH1 mutants showed markedly stalled epithelial differentiation, while TP53 mutants combined impaired differentiation with increased proliferation, conferring greater fitness. Clonal diversity increased with age, and loss of heterozygosity of NOTCH1 further amplified early-state biases. By connecting genotype and phenotype at single-cell resolution, this work demonstrates how largely single-driver clones expand while maintaining tissue structure, illuminating early steps in epithelial oncogenesis.See article, p. 721.Stahlhut and colleagues report the discovery of BBO-11818, a potent, selective, orally bioavailable noncovalent pan-KRAS inhibitor capable of targeting multiple KRAS mutants in both the inactive GDP-bound (OFF) and active GTP-bound (ON) states. By binding the Switch-II/Helix-3 pocket to disable effector engagement and block SOS-mediated nucleotide exchange, BBO-11818 was effective across multiple clinically significant KRAS mutations, including G12D and G12V. BBO-11818 potently inhibited MAPK signaling and viability in KRAS-driven cancer models and led to tumor regressions in KRAS-mutant colorectal, pancreatic, and lung xenografts. Combination therapy with anti–PD-1, anti-EGFR antibodies, or a RAS:PI3Kα breaker deepened responses and enhanced immune activation. By targeting both the ON- and OFF-state conformations, BBO-11818 offers a broadly effective strategy for overcoming KRAS-driven oncogenesis and therapeutic resistance.See article, p. 740.Ji, Ju, Chen, and colleagues provide evidence that serotonin metabolism regulates lineage plasticity in neuroendocrine prostate cancer. Tumors upregulate DDC and SLC6A4 to elevate intracellular serotonin, which the enzyme TGM2 converts into H3K4me3Q5 serotonylation that stabilizes active chromatin, activates SOX9 and ASCL1 programs, and suppresses androgen receptor signaling. Genetic or pharmacologic blockade of this axis reduced neuroendocrine markers, proliferation, and tumor burden across organoids, xenografts, a triple-knockout mouse model, and a patient-derived xenograft. The FDA-approved DDC inhibitor carbidopa lowered serotonin, diminished H3K4me3Q5ser, and prolonged survival. High DDC/TPH1 expression and neuroendocrine status stratified sensitivity, nominating histone serotonylation as a tractable therapeutic vulnerability.See article, p. 760.Through in vivo CRISPR screening, Sreekumar and colleagues identified SOX5 as a central regulator of breast cancer dormancy. Loss of Sox5 accelerated recurrence locally and in lung metastases by permitting dormant residual tumor cells to reenter the cell cycle. Dormant cells strongly upregulated a SOX5-dependent endochondral ossification program, confirmed by transcriptomic analysis, histologic staining, and [18F]NaF PET imaging. This calcified, low-proliferation niche contrasted sharply with adjacent recurrent outgrowths. Patient datasets showed that osteochondrogenic signatures increase after neoadjuvant therapy and predict improved recurrence-free survival. These findings position SOX5-mediated ossification as a clinically relevant dormancy-enforcing mechanism.See article, p. 781.Lee Jr, Zhang, and colleagues reveal that LINE-1 retrotransposons regulate cancer gene expression by shaping 3D genome architecture. Subcellular transcriptomic analyses found that LINE-1 RNAs were nascent, nuclear, and chromatin-bound, arising from evolutionarily young, cell-type–specific loci under lineage-selective transcription factors such as FOXA1. A long-read chromosome conformation assay defined highly interactive LINE-1 loci that formed chromatin hubs with active regulatory DNA and linked oncogenes. Antisense depletion of LINE-1 RNAs collapsed these interactions, downregulated MYC and KRAS programs, and impaired proliferation, while a single inducible LINE-1 knock-in created de novo long-range chromatin loops. Together, this study sheds light on a mechanism by which LINE-1 transcripts engage with RNA binding proteins to scaffold hubs that sustain oncogenic transcription.See article, p. 800.