Cancer Discov
· 2026 May · PMID 42084533
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Clonal hematopoiesis (CH) - the expansion of genetic variants in blood - is a prime example of somatic evolution. Although it often precedes malignant transformation, many aspects of this process remain unknown. We show...Clonal hematopoiesis (CH) - the expansion of genetic variants in blood - is a prime example of somatic evolution. Although it often precedes malignant transformation, many aspects of this process remain unknown. We show that a model of polyclonal competition, in which selectively-advantaged clones continually appear and compete, explains observed CH dynamics throughout human life. We quantify the fitness distribution and occurrence rate of clonal expansions using either variant trajectories or HSC genetic heterogeneity. Inferences on both data converge. Approximately three fit clones enter the HSC pool per year, yet rarely more than five achieve >1.5% frequency throughout life. The fittest clones emerge predominantly later in life in accordance with a multistep evolutionary process. DNMT3A-variants were enriched for single-hit clones, whereas TET2, ASXL1, JAK2, SF3B1, and SRSF2 showed enrichment for multi-hit evolution. These findings suggest precursors of hematological malignancies are identifiable prior to transformation and may facilitate early intervention strategies.
Cancer Discov
· 2026 Jun · PMID 42084243
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On April 26, 1986, Reactor Number 4 at the Chernobyl Nuclear Power Plant exploded, releasing massive amounts of radioactive material into the atmosphere. Exposed children contracted papillary thyroid carcinoma at elevate...On April 26, 1986, Reactor Number 4 at the Chernobyl Nuclear Power Plant exploded, releasing massive amounts of radioactive material into the atmosphere. Exposed children contracted papillary thyroid carcinoma at elevated rates, and on the eve of the 40-year anniversary, many studies are now focused on the transgenerational health effects of the disaster.
Cancer Discov
· 2026 Jun · PMID 42068538
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Among 74 patients newly diagnosed with HER2-mutant NSCLC who received a daily dose of zongertinib, the objective response rate was 76% and the median progression-free survival was 14.4 months. That bests chemotherapy, to...Among 74 patients newly diagnosed with HER2-mutant NSCLC who received a daily dose of zongertinib, the objective response rate was 76% and the median progression-free survival was 14.4 months. That bests chemotherapy, to which about 30% of patients typically respond for less than 7 months.
Cancer Discov
· 2026 May · PMID 42063320
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In this issue of Cancer Discovery, Nigri and colleagues identify myofibroblastic cancer-associated fibroblasts as drivers of sympathetic nerve recruitment and activation in pancreatic ductal adenocarcinoma. By uncovering...In this issue of Cancer Discovery, Nigri and colleagues identify myofibroblastic cancer-associated fibroblasts as drivers of sympathetic nerve recruitment and activation in pancreatic ductal adenocarcinoma. By uncovering a feedforward stromal-sympathetic circuit, the study establishes neuroplasticity as a fibroblast-orchestrated and therapeutically targetable process that is likely applicable across multiple cancer types. See related article by Nigri et al., p. 1014.
Cancer Discov
· 2026 May · PMID 42063319
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Roy and colleagues describe VVD-065, a covalent allosteric molecular glue that binds KEAP1 at Cys151 to enhance KEAP1-CUL3 assembly, restore NRF2 ubiquitination and degradation, and selectively suppress NRF2-driven tumor...Roy and colleagues describe VVD-065, a covalent allosteric molecular glue that binds KEAP1 at Cys151 to enhance KEAP1-CUL3 assembly, restore NRF2 ubiquitination and degradation, and selectively suppress NRF2-driven tumors by reactivating endogenous E3 ligase function. See related article by Roy et al., p. 953.
Cancer Discov
· 2026 May · PMID 42063318
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Immune checkpoint inhibitors have revolutionized cancer therapy, and their unintended side effects relate largely to inducing autoimmunity; effects on vascular functions have only rarely been observed so far. In this iss...Immune checkpoint inhibitors have revolutionized cancer therapy, and their unintended side effects relate largely to inducing autoimmunity; effects on vascular functions have only rarely been observed so far. In this issue of Cancer Discovery, a puzzling finding is reported that has divergent clinical implications: PD-1 inhibitors make cytotoxic T lymphocytes secrete a Wnt pathway suppressor to the blood that opens the blood-brain barrier, both allowing circulating tumor cells to enter the brain and a chemotherapeutic to better reach tumor cells in brain metastases. See related article by Deo et al., p. 976.
Fujino T, Lewis J, Chen B
… +36 more, Feinberg TY, Maron MI, Lewis AM, Wishnack C, Sievers Q, Kaito S, Cai W, Yoo S, Mathew SC, Souness S, Burns E, Um J, de Stanchina E, Chang Q, Qeriqi B, Chen K, Zhang P, DeWolf S, Weinreb JT, Mammone R, Miranda IC, Stanley RF, Cuibus MA, Weis K, Gipson B, Castro C, Fox N, Lee MS, Alvarez-Perez J, You D, Dela Cruz FS, Fronk AD, Akerman M, Kung AL, Abdel-Wahab O, Daniyan AF
Cancer Discov
· 2026 Apr · PMID 42059863
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Developing chimeric antigen receptor (CAR) T cells for acute myeloid leukemia (AML) has been challenging due to a lack of known AML-associated antigens that spare normal hematopoietic precursor cells. Here we reasoned th...Developing chimeric antigen receptor (CAR) T cells for acute myeloid leukemia (AML) has been challenging due to a lack of known AML-associated antigens that spare normal hematopoietic precursor cells. Here we reasoned that donor autoantibodies from AML recipients cured following allogeneic transplant and responsible for graft-versus-leukemia effect could be engineered to create effective CAR-T cells. We generated CAR-T cells against one such antigen - U5 snRNP200, an RNA helicase localized to the AML cell surface and absent from normal hematopoietic precursors. Anti-U5 snRNP200 CAR-T cells were effective in human and syngeneic models of AML as well as B-cell acute lymphoblastic leukemia (B-ALL), a setting where surface U5 snRNP200 is also present. Armoring CAR-T cells with IL-18 led to antigen gain on AML, durable remission, and protection from AML rechallenge. These data thereby identify a CAR-T cell platform which addresses prior limitations in tumor-selectivity and safety for patients with acute leukemias.
Cancer Discov
· 2026 Jun · PMID 42057455
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At the American Association for Cancer Research Annual Meeting, researchers presented data from three separate phase I studies investigating distinct mesothelin-targeted chimeric antigen receptor T-cell therapies: SynKIR...At the American Association for Cancer Research Annual Meeting, researchers presented data from three separate phase I studies investigating distinct mesothelin-targeted chimeric antigen receptor T-cell therapies: SynKIR-110, UCMYM802, and M28z1XXPD1DNR.
Ruiz CF, Ge X, McDonnell R
… +18 more, Agabiti SS, McQuaid DC, Tang A, Kharwa M, Goodell J, Saavedra-Pena RDM, Wing A, Li G, Medici NP, Robert ME, Varshney RR, Rudolph MC, Gorelick FS, Wysolmerski J, Canals D, Haley JD, Rodeheffer MS, Muzumdar MD
Cancer Discov
· 2026 Apr · PMID 42053430
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High-fat diet (HFD) intake has been linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC), a lethal and therapy-resistant cancer. However, whether and how specific dietary fats drive cancer development r...High-fat diet (HFD) intake has been linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC), a lethal and therapy-resistant cancer. However, whether and how specific dietary fats drive cancer development remains unresolved. Leveraging an oncogenic Kras-driven mouse model that closely mimics human PDAC progression, we screened a dozen isocaloric HFDs differing solely in fat source and representing the diversity of human fat consumption. Unexpectedly, diets rich in oleic acid - a monounsaturated fatty acid (MUFA) typically associated with good health - markedly enhanced tumorigenesis. Conversely, diets high in polyunsaturated fatty acids (PUFAs) suppressed tumor progression. Relative dietary fatty acid saturation levels (PUFA/MUFA) governed pancreatic membrane phospholipid composition, lipid peroxidation, and ferroptosis sensitivity in mice, concordant with circulating PUFA/MUFA levels being linked to altered PDAC risk in humans. These findings directly implicate dietary unsaturated fatty acids in controlling ferroptosis susceptibility and tumorigenesis, supporting potential "precision nutrition" strategies for PDAC prevention.
Cancer Discov
· 2026 Jun · PMID 42053097
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The molecular glue degrader field is growing rapidly, with multiple next-generation candidates in development. Some are targeted against culprit proteins not readily accessible to small-molecule inhibitors, such as ARNT;...The molecular glue degrader field is growing rapidly, with multiple next-generation candidates in development. Some are targeted against culprit proteins not readily accessible to small-molecule inhibitors, such as ARNT; others aimed at ALK, for instance, may help address the resistance to existing tyrosine kinase inhibitors that inevitably occurs.