Highlighted Research Articles

Baldacci, Brea, Facchinetti, and colleagues identify TROP2 as a target enriched on EGFR-mutant lung cancer cells that survive EGFR tyrosine kinase inhibition. However, co-treatment of EGFR-mutant tumors with osimertinib and sacituzumab govitecan, a TROP2 antibody–drug conjugate therapy, is incapable of eliminating these drug-tolerant persister cells, with universal relapse. In contrast, a single infusion of sacitizumab-based CAR T cells administered with osimertinib at the time of induced minimal residual disease produces durable responses with evidence of cure. Additional CAR T-cell engineering may enhance efficacy and minimize toxicity, paving the way towards eliminating drug-tolerant persister cells in patients.See article, p. 2235.Farooq and colleagues examined demographic trends among 16,609 patients, 15,308 of whom were U.S. residents, enrolled in the National Cancer Institute’s Cancer Therapy Evaluation Program–sponsored early-phase trials from 2000 to 2023. Enrollment rose among patients aged 65 to 74 and 75 to 84 years and among Hispanic/Latino, Asian/Pacific Islander, and non-Hispanic Black participants. However, representation remained below cancer incidence rates for Hispanic/Latino and non-Hispanic Black patients and was negligible for American Indian/Alaska Native populations. Enrollment improved after the 2014 Experimental Therapeutics Clinical Trials Network launch, coinciding with reduced travel distance to enrolling sites. These findings highlight progress and persistent gaps, informing strategies to broaden equitable participation in oncology trials.See article, p. 2251.Ovarian high-grade serous carcinoma (HGSC), the deadliest gynecologic malignancy, is characterized by prevalent chromosomal instability that drives extensive genomic heterogeneity. Micoli and colleagues established chromosomal instability signatures from more than 600 whole-genome sequenced tumors to dissect HGSC heterogeneity and discovered five robust molecular subtypes with clinical relevance. Two subtypes reflected BRCA1- and BRCA2-driven alterations, whereas three subtypes described patients who were resistant to chemotherapy but displayed unique and targetable genomic alterations, transcriptional profiles, and pathways. Organoid experiments further revealed subtype-specific vulnerabilities and highlighted CHK1 inhibition as a potentially promising therapy for patients with currently untreatable HGSC.See article, p. 2262.Gut microbiota composition has been linked with immune checkpoint blockade (ICB) efficacy. However, the impact of dietary components such as non-nutritive sweeteners on the efficacy of ICB remains unclear. Evaluating patients with ICB-treated melanoma and lung cancer, Morder, Nguyen, Wilfahrt, and colleagues demonstrated that sucralose consumption at levels below acceptable daily intake thresholds impacted ICB efficacy. In preclinical models, sucralose modified microbiome composition by reducing microbiota-accessible arginine, resulting in diminished T-cell metabolism and function and reduced ICB efficacy.See article, p. 2278.Selective targeting of cancer stem cells offers a promising route to cure cancer. Shen, Che, Zhou, Wang, Li, Xue, and colleagues showed that the RNA demethylase ALKBH1 promoted tumorigenesis, leukemia stem cell (LSC) self-renewal, and therapy resistance through tRNA modification and codon decoding. ALKBH1 installed 5-formylcytidine (f5C) at tRNA wobble positions. The subsequent reprogramming of tRNA pools broadened codon recognition and boosted protein synthesis, thereby sustaining LSC self-renewal and resistance to venetoclax. Inhibition of ALKBH1 suppressed LSC function and leukemia progression while sparing normal hematopoiesis and synergized with venetoclax in preclinical models of acute myeloid leukemia. These findings highlight ALKBH1 as a compelling therapeutic target in cancer.See article, p. 2298.The standard of care for triple-negative breast cancer (TNBC) includes frontline chemotherapy via taxanes and other microtubule-targeting agents. However, not all tumors respond to taxane therapy, and the molecular mechanisms that underlie sensitivity to taxanes remain incompletely understood. Neill, Satpathy, and colleagues utilized integrative proteomics and forward genetics to screen for mediators of taxane sensitivity in TNBC, leading to the identification of the tumor suppressor PTPN12, which when inactivated resulted in the hyperactivation of the ubiquitin ligase complex APCFZR1. Elevated APCFZR1 activity subsequently generated mitotic stress that conferred a therapeutic vulnerability of PTPN12-inactivated TNBCs to taxane treatment.See article, p. 2326.Through a gain-of-function cDNA screen, Sinha and colleagues demonstrated that KRAS/TP53-mutant pancreatic tumor cells utilized GCN1 stress signaling to drive compensatory metabolic reprogramming and escape immune recognition by downregulating natural killer (NK) ligands and major histocompatibility class I expression. Targeting GCN1 with IMPACT, a biological inhibitor frequently lost in aggressive tumors, not only disrupted tumor cell metabolic homeostasis but also augmented tumor immunogenicity to unleash robust NK cell killing, in addition to sensitizing tumor cells to immune checkpoint blockade. These findings identify GCN1 signaling as an immunometabolic dependency and a promising therapeutic target in metastatic cancers.See article, p. 2344.The role of “off-pore” nucleoporins in solid tumors remains largely unknown. Kirthika, Jawalagatti, Li, and colleagues showed that the expression of the nucleoplasm-residing nucleoporin, sPOM121 increased during prostate cancer disease progression. Combined proteomic, transcriptomic, and epigenomic studies revealed that sPOM121 enhanced oncogenic signaling, through its interaction with chromatin remodelers at nuclear onco-condensates, promoting therapy resistance and immune evasion. Inhibition of sPOM121-driven oncogenic signaling pathways, such as β-catenin, sensitized tumors to chemo-hormonal and immune checkpoint therapy, supporting the potential of interfering with off-pore, nucleoplasm-localized nucleoporins as a new therapeutic avenue in solid tumors.See article, p. 2374.