Editors’ Picks, September 2026: Drug Resistance, Breast Cancer Treatment, COVID-19 and Cancer Care, and More
With school back in session, take a moment to educate yourself on some of the latest advances in cancer research published in the ten peer-reviewed journals of the American Association for Cancer Research (AACR). This month’s Editors’ Picks include insights into cancer evolution in leukemia, a strategy for overcoming drug resistance, the impacts of the COVID-19 pandemic on cancer care, an investigational treatment for triple-negative breast cancer, and more.
Keep reading for the abstracts of the highlighted studies, and follow the links for the full-text articles, freely available for a limited time.
Journal: Blood Cancer Discovery
RAS Pathway Activation and Microenvironmental Adaptation as Hallmarks of Myeloid Sarcoma
Myeloid sarcoma, an aggressive extramedullary subtype of acute myeloid leukemia (AML), occurs in approximately 20% of patients and remains strikingly understudied in large-scale genomic and multiomic investigations. The key drivers of its tumor evolution are largely unknown; timely detection in asymptomatic patients poses a clinical challenge, and effective treatment options are limited, as patients are often excluded from clinical trials, rendering it a largely neglected disease entity. In this study, we demonstrate that myeloid sarcoma evolves from medullary AML but exhibits distinct site-specific clonal evolution. This is supported by unique transcriptional signatures of myeloid sarcoma, reflecting adaptation to the extramedullary microenvironment. We establish a proof of concept that circulating tumor DNA (ctDNA) sequencing captures the molecular composition of myeloid sarcoma, offering a potential noninvasive approach for molecular profiling of extramedullary AML. Our findings highlight marked differences between medullary AML and myeloid sarcoma, including universal molecular evolution and RAS pathway activation as disease hallmarks.
Significance: We provide a comprehensive multiomic characterization of myeloid sarcoma, identifying key molecular pathways that contribute to its development, and suggest ctDNA as a noninvasive method of detection. We identify RAS pathway activation and transcriptional adaptation to the solid tissue microenvironment as cardinal features of myeloid sarcoma, suggesting novel therapeutic avenues.
Learn more about the development and evolution of AML: Bloodlines Series: Mapping the Many Paths of Acute Myeloid Leukemia
Journal: Cancer Discovery
Despite successful immuno-oncology therapies in other cancers, they have largely failed in glioblastoma (GBM). In this study, natural killer (NK) cells from patients with glioma show impaired oxidative phosphorylation and mitochondrial complex I activity. Multiomics profiling identified complex I subunit NDUFA9 as a critical mediator of NK cell metabolic fitness. The abundance of NDUFA9+ NK cells informed patient outcomes. Ndufa9 knockout in NK cells compromised mitochondrial function, antitumor efficacy, and the memory-like phenotype of NK cells by triggering a metabolic reprogramming toward glutamine dependence. The decreased α-ketoglutarate/succinate ratio in Ndufa9-deficient NK cells mediated widespread epigenetic reprogramming by inducing the transcriptionally repressive histone mark H3K27me3 on key immune function genes. Resveratrol-mediated NDUFA9 activation or its overexpression enhanced NK cell anti-GBM function by restoring complex I activity. Together, these findings reveal the critical role of mitochondrial complex I activity in NK cells and highlight its potential as an actionable target to enhance NK cell–based immunotherapy for patients with GBM.
Significance: This study reveals that NDUFA9 deficiency in mitochondrial complex I compromises metabolic fitness and impairs the antitumor activity of NK cells in GBM. We identify the mitochondrial complex I subunit NDUFA9 as a key pharmacologically targetable node for NK cell–based immunotherapy in GBM, leveraging metabolic reprogramming to enhance antitumor efficacy.
A related commentary was published in the September issue, where this article was also featured on the cover.
Journal: Cancer Epidemiology, Biomarkers & Prevention
Background: Public health emergencies can substantially affect routine health care. Large cancer screening declines during the early months of the COVID-19 pandemic are well documented; however, COVID-19’s impact on follow-up of abnormal screening exams and cancer diagnoses is less reported. We examined the impacts of COVID-19 on the cervical, colorectal, and lung cancer screening processes, within 10 health systems in the Population-based Research to Optimize the Screening Process (PROSPR) consortium.
Methods: PROSPR data were used to calculate: (i) monthly rates of cancer testing and, for pre-COVID and COVID time periods, (ii) proportions of individuals receiving recommended follow-up within 6 months of an abnormal test, and (iii) cancer incidence. Surveys were used to assess the healthcare systems’ local context.
Results: During the first 2 months of the pandemic, cancer testing decreased across all health systems and cancer types (range, 18%–96%). Overall, decreases in monthly rates were followed by rapid recovery to prepandemic rates. The rates of 6-month follow-up of abnormal screening results trended down in the COVID versus pre-COVID periods, as did the diagnosis of new cancers.
Conclusions: Declines in cancer testing in the early months of the COVID-19 pandemic were short term, with at least short-term impacts on diagnostic follow-up and cancer diagnosis. The systems with the smallest decreases were those that both utilized remote screening outreach (e.g., mailed fecal immunochemical test kits) and did not pause that outreach at the start of the pandemic.
Impact: Strategies and policies implemented by healthcare systems during public health emergencies can help minimize disruptions in care.
A related commentary was published in the September issue, where the article was also highlighted.
Learn more about the impact of the COVID-19 pandemic on cancer screening and care: AACR COVID-19 and Cancer Report: Patients, Policymakers, and Researchers Share Their Stories
Journal: Cancer Immunology Research
Pancreatic cancer responds poorly to immunotherapy, primarily due to poor activation of CD8+ T cells and their limited infiltration into the tumor tissue. Strategies to enhance CD8+ T-cell priming and function are therefore critical for improving immunotherapeutic efficacy in pancreatic cancer. The RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) plays a pivotal role in maintaining immune homeostasis. In this study, we found that ADAR1 expression positively correlates with pancreatic cancer progression. Depletion of ADAR1 in tumor cells resulted in excessive production of interferon β, which increased the abundance and activation of conventional type 1 dendritic cells. This alteration enhanced CD8+ T-cell recruitment and activation, ultimately sensitizing pancreatic cancer to immunotherapy. Collectively, our findings support ADAR1 inhibition combined with immunotherapy as a promising therapeutic strategy for pancreatic cancer.
Learn more about advances in pancreatic cancer research: Pancreatic Cancer: The Search for an Achilles Heel
Journal: Cancer Prevention Research
Screening for pathogenic variants (PV) associated with hereditary cancer syndromes has a positive impact on public health by identifying patients at risk of developing the associated cancers. This survey assesses the current practice of screening for hereditary cancer syndromes and the acceptability of chatbot utilization among primary care providers and residents in rural Southwest Virginia. A two-part survey was conducted among primary care providers and residents in rural Southwest Virginia to assess demographics, health practices, genetic screening practices, and interest in chatbot technology in a geographically underserved population. The response rates for the provider and resident surveys were 8.9% and 19.9%, respectively. A total of 66 providers responded to the survey. One third (32.3%) of providers in our study never screen for hereditary cancer syndromes, and almost two thirds (63.1%) screen their patients for cancer syndromes less than half the time. About 77% of providers felt that chatbots would be useful in identifying patients who need testing and directing what testing to order. Surveys of 476 residential responders showed that 81.9% of residents felt that chatbot technology sounds somewhat to very useful for genetic screening and counseling. More than 57% of residents noted that they would feel comfortable with utilizing chatbot technology to discuss results of genetic screening. Residents and their providers in geographically underserved populations are interested in using chatbots to improve access to genetic testing. Implementation of technology, such as chatbots, in these underresourced settings has the potential to amplify access to genetic counseling and testing.
Prevention Relevance: This article describes survey results for acceptability of using chatbots for assessing risk and early detection of PVs associated with hereditary cancer syndromes in a rural population. The results could guide further implementation of technology in assisting with early detection and prevention of hereditary cancer syndromes..
This article was featured on the cover of the September issue.
Learn how artificial intelligence-powered tools may transform clinical care: Eye on AI: AI Agents as Doctors’ Deputies in the Cancer Clinic
Journal: Cancer Research (September 1 issue)
A population of cells within a tumor can be described as antifragile (the opposite of fragile) if they derive a benefit from fluctuations or perturbations in environmental conditions induced by treatment. Treatment fluctuations could either promote (antifragile tumor) or inhibit (fragile tumor) the evolution of treatment resistance to targeted therapies. In this study, we showed that analysis of the convexity of dose–response curves provided a direct prediction of response to prescribed fluctuations in treatment. Convexity predicted that continuous treatment protocols (i.e., zero prescribed fluctuations in treatment) would outperform uneven protocols when dose response is convex. This theory was applied to predict in vivo response to targeted therapy, and the predictions were validated by experimentally testing high/low intermittent dosing (uneven dosing) and continuous dosing (even dosing) schedules. Convexity (and its inverse, concavity) explained 2 phenomena: Dose response is a convex (fragile) function, but the resistance onset rate is a concave (antifragile) function. Thus, design and validation of alternative treatment schedules maximized response while maintaining prolonged sensitivity to treatment. Together, these analyses provide supporting evidence that fluctuations alter the evolutionary trajectory of tumors in response to targeted therapy, even without altering the cumulative dose. By using this insight to design alternative treatment protocols to limit the evolution of resistance by careful analysis of the dose–response curvature, the study supports the potential of “evolutionary antifragile therapy” as a subtype in the broad class of evolution-based treatment strategies.
Significance: The mathematical method using dose response curvature to determine appropriate treatment dosing that limits the evolution of resistance could facilitate designing dose schedules that optimize tumor response.
A related commentary was published in the September 1 issue.
Journal: Cancer Research (September 15 issue)
KLF4 Promotes a KRT13+ Hillock-Like State in Lung Squamous Cell Carcinoma
Lung squamous cell carcinoma (LUSC) is a basal-like subtype of lung cancer with limited treatment options. Although prior studies have identified tumor-propagating cell (TPC) states in squamous tumors, further work is needed to elucidate the broader landscape of intratumoral heterogeneity within LUSC. In this study, we employed SOX2-driven mouse models, organoid cultures, and single-cell transcriptomic analyses to uncover cell fate diversity within LUSC, identifying a KRT13+ hillock-like population of slower-dividing tumor cells characterized by immunomodulatory gene expression signatures. The tumor hillock-like state was conserved across multiple animal and human-derived models and was computationally predicted in the majority of human LUSCs, as well as in head and neck and esophageal squamous tumors. Analysis of the cellular origins of tumor hillock-like states indicated that lung club cells give rise to tumors with luminal hillock-like populations, whereas basal-like TPCs transition into basal hillock-like states, resembling lineage plasticity trajectories of the normal lung. Mechanistically, Kruppel-like factor 4 (KLF4) promoted the KRT13+ hillock-like state and contributed to resistance to oxidative stress and platinum-based chemotherapy in vitro. Together, these results provide molecular insights into the lineage plasticity underlying intratumoral heterogeneity within LUSC, offering potential avenues for new therapeutic strategies.
Significance: KLF4 drives a slow-cycling, KRT13+ hillock-like state that is plastic with basal lineages, promoting intratumoral heterogeneity in lung squamous cell carcinoma and conserved across squamous cancers, with potential implications for treatment resistance.
A related commentary was published in the September 15 issue.
Journal: Clinical Cancer Research (September 1 issue)
Purpose: Human epidermal growth factor receptor 2 (HER2) mutations occur in 1% to 3% of triple-negative breast cancers (TNBC), representing a novel target for biomarker-directed treatment. In the SUMMIT basket trial (NCT01953926), patients with HER2-mutant, metastatic TNBC received neratinib (240 mg/day) or neratinib + trastuzumab (N + T; neratinib 240 mg/day, intravenous trastuzumab 8 mg/kg initially and then 6 mg/kg every 3 weeks). We report final results from the neratinib and N + T TNBC cohorts.
Patients and Methods: Primary endpoint: investigator-assessed objective response rate at first postbaseline tumor assessment (ORRfirst); secondary endpoints included confirmed ORR by investigator, clinical benefit rate (CBR), and progression-free survival (PFS); exploratory endpoint included circulating tumor DNA (ctDNA) collected at baseline, during treatment, and at the end of treatment.
Results: Twenty-seven patients were enrolled between July 2014 and September 2021. Confirmed ORRs were 40% [95% confidence interval (CI), 12.2−73.8] for neratinib (n = 10) and 35.3% (95% CI, 14.2−61.7) for N + T (n = 17). CBRs were 40% (95% CI, 12.2−73.8) and 47.1% (95% CI, 23−72.2), respectively; median PFS times were 2.89 (95% CI, 0.95−5.52) and 6.24 months (95% CI, 2.10−8.18), respectively. HER2 mutation variant allele frequencies in ctDNA from patients with response or stable disease decreased upon treatment and increased upon progression. Serial ctDNA sequencing revealed emergence or increase in on-pathway (ERBB3) and off-pathway (KRAS and TP53) mutations. The most common treatment-emergent adverse events were diarrhea, nausea, and constipation.
Conclusions: N + T in patients with HER2-mutant metastatic TNBC seemed to prolong responses versus neratinib alone, representing a novel approach for patients with biomarker-defined metastatic TNBC. Based on these and previously published data, neratinib-based combinations are endorsed by the National Comprehensive Cancer Network guidelines for patients with hormone receptor–positive or –negative metastatic breast cancer with activating HER2 mutations.
A related commentary was published in the September 1 issue.
Learn more about the treatment of TNBC: Experts Explore How to Treat Each Stage of Triple-negative Breast Cancer
Journal: Clinical Cancer Research (September 15 issue)
Purpose: Outcomes for children with relapsed and refractory neuroblastoma are dismal. ENCIT-01 (NCT 02311621) was a first-in-human clinical trial for patients with relapsed and refractory neuroblastoma using chimeric antigen receptor (CAR) T cells targeting L1CAM, an adhesion molecule that is overexpressed in neuroblastoma with limited normal tissue expression.
Patients and Methods: This trial evaluated three different CAR constructs: a short-spacer second-generation 4-1BB CAR (2GS, arm A), a short-spacer third-generation 4-1BB + CD28 CAR (3GS, arm B), and a long-spacer second-generation 4-1BB CAR (2GL, arm C).
Results: Thirty-six patients were enrolled, of whom 22 were treated (arm A/2GS n = 11, arm B/3GS n = 8, and arm C/2GL n = 3). Thirty-four of 36 patients had a CAR T-cell product successfully manufactured. Cytokine release syndrome, skin rash, and hyponatremia were common ≥ grade 2 toxicities. Hyponatremia was dose-limiting in three patients [dose level (DL); DL5 arm A/2GS, DL3 arm B/3GS, and DL2 arm C/2GL]. Patterns of toxicity appeared at lower DLs on arms B and C compared with arm A, suggesting differential potency of the third generation and long-spacer products. No objective responses were seen. Correlative analyses demonstrated CAR T-cell presence in tumor and skin, with evidence of macrophage tumor infiltration.
Conclusions: Although feasible to manufacture in a heavily pretreated population, L1CAM may not be an appropriate target in neuroblastoma. Additional engineering strategies may be needed to prevent toxicity and provide durable antitumor effects.
This article was featured on the cover of the September 15 issue.
Journal: Molecular Cancer Research
Lung adenocarcinoma (LUAD), the most common subtype of lung cancer, is a heterogeneous disease with highly variable histopathologic features and clinical outcomes. LUAD premalignant lesions (PML) are localized proliferations of atypical pneumocytes that spread along the alveolar walls. In this study, we characterized the molecular heterogeneity across PMLs, regardless of histologic classification, and identified four distinct groups or “archetypes” of PMLs using bulk RNA and DNA exome sequencing data from laser-captured microdissected PMLs, normal, and tumor tissues from LUAD resection cases. The archetypes were defined by recurrent gene coexpression modules discovered using the LUAD PMLs we profiled and three publicly available datasets. One PML archetype, termed “proliferation,” was associated with increased expression of genes involved in cell proliferation, a protumor immune environment, and enrichment for EGFR driver mutations. In contrast, the “normal-like” archetype exhibited molecular features similar to normal tissue, an antitumor immune response, and lacked driver mutation enrichment. We projected the PML archetypes into independent gene expression datasets profiling LUAD and found that tumors closest to the proliferation archetype were enriched for multiple features of aggressive LUAD, including high tumor grade and lymph node invasion, and were significantly associated with shorter disease-free survival. Proliferation archetype PMLs may represent a subset of lesions with increased malignant potential and may provide opportunities to improve patient stratification and identify novel targets for lung cancer interception.
Implications: Molecular signatures that distinguish indolent from aggressive LUAD PMLs may help personalize lung cancer screening and interception protocols.
This article was highlighted in the September issue.
Journal: Molecular Cancer Therapeutics
Tumor-targeting antibodies, antibody–drug conjugates, and radionuclide antibody conjugates are established therapeutic tools in clinical use. Furthermore, bispecific T cell–engaging antibodies (TCEs) and chimeric antigen receptor (CAR) T cells are becoming the clinical standard of care in hemato-oncology and in some solid tissue neoplasms. To allow for on–off switching and targeting of multiple antigens, CAR T cells designed to recognize tumor-bound adaptor molecules (adaptor-CAR T cells) are now being investigated in clinical trials. We hypothesized that like adaptor-CAR T cells, a bispecific TCE recognizing CD3ε on T cells and fluorescein on tumor-bound adaptors would be able to direct T cells against target cells, potentially enabling multiplexing. We here show that a newly generated single-chain Fv-based anti-CD3 × anti-FITC construct (AdFITC-TCE) activates T cells toward acute myeloid leukemia (AML). Recognition of multiple targets through binding to fluoresceinated antibody constructs against CD33 and CD117 enables efficient tumor cell lysis in vitro. Moreover, we demonstrate that AdFITC-TCE plus fluoresceinated adaptors and T cells inhibit AML cell growth in NOD.Cg-Prkdcscid Il2rgtm1WjI/SzJ mice in vivo with similar efficacy as AdFITC-CAR T cells. Together, these data suggest that AdFITC-TCE, in combination with any given fluoresceinated binder, might be a versatile tool to activate T cells, leading to respective target cell lysis.
This article was highlighted in the September issue.
Learn about bispecific T-cell engagers: Taking a BiTE Out of Cancer
Journal: Cancer Research Communications
Glioblastoma Subtypes Exhibit Distinct Migration Mechanics and Immune Responses
Glioblastoma (GBM) remains a deadly cancer driven in part by invasion of tumor cells into the brain. Transcriptomic analyses have identified distinct molecular subtypes, but mechanistic differences that account for clinical differences are not clear. In this study, we show that, as predicted by the motor-clutch model of cell migration, mesenchymal glioma cells are more spread, generate larger traction forces, and migrate faster in brain tissue compared with proneural cells. Despite their rapid migration and comparable proliferation rates in vitro, mice with mesenchymal tumors survive longer than those with proneural tumors. This improved survival correlated with an immune response in mesenchymal tumors, including T cell–mediated. Consistently, inducing mesenchymal tumors in immunodeficient mice resulted in shorter survival, supporting a protective immune role in mesenchymal tumors. Thus, mesenchymal tumors have aggressive migration but are immunologically “hot,” which suppresses net proliferation. These two features counteract each other and may explain the lack of a strong survival difference between subtypes clinically, while also opening up new opportunities for subtype-specific therapies.
Significance: This study highlights new mechanical and immunologic insights into GBM molecular subtypes using an integrated modeling–genome engineering strategy, which can potentially facilitate GBM subtype-specific therapeutic strategies.
