The N-terminal domain of VGF is required for sustaining mitochondrial fusion and oxidative phosphorylation to support metabolic adaptation in lung cancer brain metastases, underscoring a potentially targetable mechanism to impair brain colonization.

KO-2806 salvages RAS inhibitor activity by controlling parallel mTORC1 in RAS inhibitor-resistant tumors in which vertical inhibition of MAPK is insufficient to restore sensitivity, providing a combination strategy for resistant patients.

SETD2 is frequently mutated or deleted in clear cell renal cell carcinoma (ccRCC). Loss of SETD2 could create synthetic lethal dependencies that confer therapeutic vulnerabilities. Here, we demonstrated that SETD2 deficiency promotes cytoplasmic mitochondrial DNA (mtDNA) leakage, leading to basal activation of cGAS-STING inflammatory signaling and increased apoptotic priming. This inflammatory state upregulated the BH3-only protein NOXA, constrained MCL-1 function, and enforced a synthetic lethal dependency on the anti-apoptotic protein BCL-xL. Pharmacological inhibition of BCL-xL further amplified cGAS-STING signaling in SETD2-deficient cells through sublethal mitochondrial outer membrane permeabilization, resulting in increased mtDNA release and robust NOXA induction. Elevated NOXA neutralized the compensatory MCL-1-mediated survival signaling, triggering apoptosis. In contrast, SETD2 proficient ccRCC cells exhibited minimal cGAS-STING activation and failed to induce NOXA following BCL-xL inhibition, rendering them resistant. Genetic ablation of cGAS, STING, IRF3, or NOXA rescued sensitivity to BCL-xL inhibition, confirming that mtDNA-driven innate immune signaling is required for this dependency. In vivo, BCL-xL inhibition suppressed tumor growth and prolonged survival in SETD2-deficient xenograft models. Collectively, these findings establish a mechanistic link between SETD2 loss, mtDNA-driven innate immune activation, and enforced BCL-xL dependence in ccRCC, revealing a therapeutically targetable vulnerability in SETD2-deficient tumors.

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.