Pancreatic ductal adenocarcinoma (PDAC) is characterized by frequent KRAS mutations, which activate the MAPK pathway to promote PDAC progression. Here, we explored metabolic vulnerabilities of PDAC by assessing initial metabolic reprogramming upon ERK inhibition using metabolomics, lipidomics, and isotope-tracing experiments. ERK inhibition enhanced lipid turnover and fatty acid oxidation while inhibiting glycolysis, glucose oxidation, and glutamine metabolism in PDAC cells. Moreover, lipophagy, but not cytosolic lipolysis, was responsible for the increased lipid turnover and fatty acid oxidation upon ERK inhibition. Lipophagy and lipophagy-fueled fatty acid oxidation were induced by increased nuclear translocation and activity of the transcription factor TFEB. Pharmacological inhibition of fatty acid oxidation in combination with KRASG12D/MEK/ERK inhibitors synergistically decreased the growth of PDAC cell lines and organoids. The combination decreased tumor burden and improved survival in orthotopic cell line and patient-derived xenograft PDAC models. Overall, this study provides mechanistic insights into the development of metabolic resistance to KRAS signaling inhibition and demonstrates that fatty acid oxidation is a metabolic vulnerability following KRAS signaling inhibition that can be utilized as an effective therapeutic target to treat PDAC.

The emergence of resistance to CDK4/6 inhibitors (CDK4/6i) is a major barrier to long-term survival in metastatic hormone receptor-positive (HR+) breast cancer. Mechanisms of CDK4/6i resistance are highly diverse and are currently unpredictable. In a recent issue of Nature, Safonov, Lee, and colleagues report that germline BRCA2 (gBRCA2) alterations predispose tumors toward loss-of-function alterations in RB1, a key mechanism of tumor escape from CDK4/6i. Leveraging large-scale clinical genomics, the authors show that gBRCA2-altered tumors are enriched for RB1 alterations and derive less benefit from CDK4/6i-based therapy, while retaining sensitivity to PARP inhibition. Mechanistically, they demonstrate that the shared location of BRCA2 and RB1 on chromosome 13q leads to RB1 hemizygosity in gBRCA2 tumors, and that homologous recombination deficiency-associated mutagenesis facilitates acquisition of a second inactivating hit. Furthermore, baseline RB1 hemizygosity predicts inferior outcomes on CDK4/6i independent of germline status, supporting its role as a predictive biomarker. These findings have immediate clinical implications regarding the sequencing of PARPi and CDK4/6i in patients with gBRCA2 mutations and highlight a potential opportunity to anticipate and intercept resistance, leading to more durable clinical benefit.

STING-high ciliated fallopian tube cells function as immune-independent active guardians of genomic integrity whose loss creates a permissive niche for high-grade serous carcinoma initiation, which could inform prevention and treatment strategies.

Brain metastasis in breast cancer patients represents a terminal disease stage, with median survival typically measured in months. Tumors that colonize the brain must adapt to its unique microenvironment, such as high acetate levels. Primary brain tumor cells enhance acetate conversion to acetyl-CoA through phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by cyclin-dependent kinase 5 (CDK5), a process regulated by the nutrient sensor O-GlcNAc transferase (OGT). In this study, we showed that brain-metastatic breast cancer cells exhibited elevated O-GlcNAc, OGT, and phosphorylated ACSS2 (Ser267) compared to their parental counterparts. Both OGT and CDK5 were essential for in vivo tumor growth in the brain, and ACSS2 and a phospho-mimetic S267D mutant drove progression of brain metastatic breast cancer. Mechanistically, ACSS2 supported tumor cell survival by suppressing ferroptosis through E2F1-dependent transcription of the anti-ferroptotic protein SLC7A11. Treatment with brain-penetrant ACSS2 inhibitor AD-5584 induced ferroptosis and significantly suppressed breast cancer brain metastatic growth ex vivo and in vivo. Together, these findings identify ACSS2 as a key metabolic regulator of brain-metastatic breast cancer survival and a promising target for ferroptosis-inducing therapies.

MYC is amplified on extrachromosomal DNA (ecDNA) or homogeneously staining regions (HSRs) in group 3 medulloblastoma (G3-MB), conferring a poor prognosis. A better understanding of the mechanisms underlying MYC expression in ecDNA and HSRs could be leveraged to develop improved treatments for G3-MB. Using a structure-function approach, we identified and characterized an enhancer (ecMYC E1) that drives MYC activation specifically in G3-MB with MYC-amplified ecDNA or HSRs. The ecMYC E1 locus exhibited enhancer hallmarks exclusively in MYC-amplified G3-MB but not in other MYC-dependent cancer cell lines, including those with MYC amplification. Silencing of the ecMYC E1 enhancer significantly reduced MYC transcription, which was compensated by increases in ecDNA copy number. NeuroD1 and BRD4 interacted with each other and bind to ecMYC E1, looping the enhancer to the MYC promoter. Together, these findings define a mechanism that regulates amplified MYC gene expression within ecDNA or HSRs specifically in G3-MB.

Aging is a major risk factor for cancer incidence and mortality, but its effect on tumor evolution and metastatic progression remains incompletely understood. A recent study by Patel and colleagues published in Nature reveals a paradoxical role for aging in cancer biology: while aging constrains primary tumor growth, it simultaneously enhances metastatic spread. Using genetically engineered mouse models and patient-derived data, the authors demonstrate that aging epigenetically reprograms mutant KRAS-driven lung adenocarcinoma through activation of the integrated stress response (ISR). Central to this process is the transcription factor ATF4, which promotes epithelial plasticity and metabolic adaptations, thereby enabling metastasis. This work provides a mechanistic framework linking host aging to tumor cell state transitions that favor distant spread of cancer cells. Importantly, it challenges a long-held assumption that tumor aggressiveness is primarily reflected by primary tumor growth kinetics and properties, and instead, it highlights metastasis as a distinct, age-influenced evolutionary trajectory. The identification of ATF4-driven ISR signaling as a mediator of metastasis highlights new therapeutic vulnerabilities, such as an acquired dependence on glutamine, particularly for older patients who comprise the majority of lung cancer cases. More broadly, this study underscores the need to incorporate aging biology into cancer models and therapeutic strategies, redefining how we conceptualize tumor progression across the lifespan.

Breast cancer remains the second leading cause of cancer-related mortality among women, with triple-negative breast cancer (TNBC) exhibiting a particularly poor five-year prognosis. Here, we demonstrated that, among genetic and pharmacological perturbations targeting DNA replication, suppression of DNA polymerase epsilon (POLE) induced a potent, TNBC-specific gene expression signature enriched in inflammatory cytokines that are transcriptional targets of NF-κB. TNBC cells exhibited markedly higher levels of DNA damage and canonical NF-κB activation compared to luminal breast cancer cells. Notably, NF-κB activation in this context depended on the canonical component RELA but not the non-canonical component RELB. Mechanistically, ATM, STING, and RIG-I each contributed to NF-κB activation following POLE suppression. POLE suppression in an in vivo murine TNBC model led to cancer cell-intrinsic elimination of tumor burden and increased immune cell infiltration. Together, these findings support a model in which replication stress from POLE inhibition triggers robust NF-κB-mediated inflammation and immune microenvironment remodeling in TNBC and can independently trigger tumor eradication. These results suggest a potential therapeutic avenue for targeting POLE in TNBC.

Abstract In pancreatic ductal adenocarcinoma (PDAC), irinotecan chemotherapy triggers a dual-phase autophagy process that drives drug resistance. Although mTOR and autophagy exert suppressive effects on each other, co-activation of mTOR and autophagy has been observed when PDAC cells begin to regrow after treatment. Therefore, we hypothesized that the distinct temporal phases of autophagy are governed by independent upstream pathways. Initially, DNA damage activated AMPK, inducing early autophagy within 24 hours that fueled fatty acid oxidation (FAO), boosting ATP production. After 48 hours, elevated ATP levels inactivated AMPK and activated mTOR, which typically suppresses autophagy. However, autophagy and FAO activity persisted beyond 72 hours of irinotecan treatment via the JNK1–Beclin-1 pathway. This created a paradoxical state in which mTOR and autophagy were co-activated, promoting cell survival under irinotecan treatment. Irinotecan combined with FAO inhibition using KN510713 (a combination of KN510 targeting the carnitine-acylcarnitine transporter and KN713 targeting acetyl-CoA acyltransferase1/2) or FAO gene knockdown blocked autophagy flux and cell growth. FAO inhibition-induced fatty acid accumulation impaired autophagy flux and induced cytotoxicity, leading to cancer cell death. In xenograft models, combining irinotecan with KN510713 significantly prevented tumor regrowth compared with irinotecan alone. These findings suggest that targeting FAO induced by autophagy activation may overcome acquired drug resistance in PDAC while minimizing the toxic side effects associated with systemic inhibition of autophagy in healthy cells.

Acquired resistance limits the therapeutic efficacy of KRAS-MAPK inhibitors in pancreatic ductal adenocarcinoma (PDAC). As transcriptional plasticity and epithelial-to-mesenchymal transition (EMT) have been implicated in resistance, we sought to study the molecular mechanisms driving these changes to uncover actionable vulnerabilities. Sustained KRAS-MAPK inhibition induced interferon and NF-κB signaling and promoted cell state change mimicking an EMT state associated with drug resistance. Network analysis identified the interferon-inducible E3 ubiquitin ligase TRIM22 as a central regulator of this response. Mechanistically, TRIM22 promoted proteasomal degradation of IκBα, resulting in sustained NF-κB and EMT program activation that coincided with a basal-like transcriptional cell state. TRIM22 expression was driven by IRF1 and IRF9 following relief of ERK-mediated transcriptional repression during pathway inhibition. EMT induction was accompanied by marked upregulation of TROP2 (TACSTD2), an NF-κB target gene enriched in basal-like PDAC cell states. Combining TROP2-directed antibody-drug conjugate sacituzumab govitecan with KRAS or ERK inhibitors significantly suppressed PDAC tumor growth in xenograft models. Overall, prolonged KRAS-MAPK inhibition activates an interferon-TRIM22-NF-κB axis that drives EMT and therapeutic resistance in PDAC, while revealing TROP2 as a clinically actionable vulnerability to overcome acquired resistance.

Abstract Microsatellite stable (MSS) rectal cancer exhibits intrinsic resistance to immunotherapy. Although radiotherapy is frequently combined with immune checkpoint inhibitors (ICIs) to augment immunotherapy responses, numerous immunologically cold tumors remain unresponsive. In this study, we observed a significant increase in electron transport chain activity, acetyl-CoA level, and global lysine acetylation level in patients achieving a pathologic complete response (pCR) following immunotherapy administered after radiotherapy. Transcriptomic screening and in vivo experiments revealed that SIRT1, a key regulator of protein acetylation, restricted the immunostimulatory effects of radiotherapy. Mechanistically, SIRT1 deacetylated DDX5, promoting unwinding of irradiation-induced R-loops and inhibiting accumulation of cytoplasmic RNA:DNA hybrids to suppress cGAS/STING pathway activation and T cell infiltration. Moreover, radiotherapy induced a tryptophan-SIRT1-SLC36A4 positive feedback loop that enhanced SIRT1 activity and promoted competitive tryptophan uptake from the microenvironment, thereby inhibiting tertiary lymphoid structure (TLS) formation and radioimmunotherapy efficacy. Finally, combining both SIRT1 inhibitor and aspirin with radiotherapy converted ICI-unresponsive rectal cancer into immunogenic tumors that were sensitive to ICI. Together, this study identifies SIRT1 as a potential biomarker and therapeutic target to overcome radioimmunotherapy resistance in MSS rectal cancer.