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Cells subjected to treatment with anti-cancer therapies can evade apoptosis through cellular senescence. Persistent senescent tumor cells remain metabolically active, possess a secretory phenotype, and can promote tumor proliferation and metastatic dissemination. Removal of senescent tumor cells (senolytic therapy) has therefore emerged as a promising therapeutic strategy. Here, using single-cell RNA-sequencing, we find that senescent tumor cells rely on the anti-apoptotic gene Mcl-1 for their survival. Mcl-1 is upregulated in senescent tumor cells, including cells expressing low levels of Bcl-2, an established target for senolytic therapy. While treatment with the Bcl-2 inhibitor Navitoclax results in the reduction of metastases in tumor bearing mice, treatment with the Mcl-1 inhibitor S63845 leads to complete elimination of senescent tumor cells and metastases. These findings provide insights on the mechanism by which senescent tumor cells survive and reveal a vulnerability that can be exploited for cancer therapy. Cell senescence remains a barrier to tumor elimination in many cancers. Here, the authors use single cell RNA-seq to identify a role for Mcl-1 in senescent cell survival, and show that Mcl-1 inhibition may be an effective therapeutic strategy.

The mechanisms by which mitochondrial metabolism supports cancer anabolism remain unclear. Here, we found that genetic and pharmacological inactivation of pyruvate dehydrogenase A1 (PDHA1), a subunit of the pyruvate dehydrogenase complex (PDC), inhibits prostate cancer development in mouse and human xenograft tumor models by affecting lipid biosynthesis. Mechanistically, we show that in prostate cancer, PDC localizes in both the mitochondria and the nucleus. Whereas nuclear PDC controls the expression of sterol regulatory element-binding transcription factor (SREBF)-target genes by mediating histone acetylation, mitochondrial PDC provides cytosolic citrate for lipid synthesis in a coordinated manner, thereby sustaining anabolism. Additionally, we found that PDHA1 and the PDC activator pyruvate dehydrogenase phosphatase 1 (PDP1) are frequently amplified and overexpressed at both the gene and protein levels in prostate tumors. Together, these findings demonstrate that both mitochondrial and nuclear PDC sustain prostate tumorigenesis by controlling lipid biosynthesis, thus suggesting this complex as a potential target for cancer therapy. Inactivation of pyruvate dehydrogenase A1 (PDHA1), a subunit of the pyruvate dehydrogenase complex (PDC) regulating mitochondrial metabolism, inhibits lipid biosynthesis and prostate cancer development in mouse and human xenograft tumor models.

Pier Paolo Pandolfi and colleagues report the generation of mice that express 80% of normal levels of the PTEN tumor suppressor. The mice develop a spectrum of tumors, including breast tumors that retain two copies of Pten , suggesting that subtle changes in expression can predispose to tumorigenesis. Cancer susceptibility has been attributed to at least one heterozygous genetic alteration in a tumor suppressor gene (TSG) 1 . It has been hypothesized that subtle variations in TSG expression can promote cancer development 2 , 3 . However, this hypothesis has not yet been definitively supported in vivo . Pten is a TSG frequently lost in human cancer and mutated in inherited cancer-predisposition syndromes 4 . Here we analyze Pten hypermorphic mice ( Pten hy/+ ), expressing 80% normal levels of Pten. Pten hy/+ mice develop a spectrum of tumors, with breast tumors occurring at the highest penetrance. All breast tumors analyzed here retained two intact copies of Pten and maintained Pten levels above heterozygosity. Notably, subtle downregulation of Pten altered the steady-state biology of the mammary tissues and the expression profiles of genes involved in cancer cell proliferation. We present an alterative working model for cancer development in which subtle reductions in the dose of TSGs predispose to tumorigenesis in a tissue-specific manner.

Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTORC1-MAPK feedback loop. We found that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with RAD001, a rapamycin derivative, showed an administration schedule-dependent increase in activation of the MAPK pathway. RAD001 treatment also led to MAPK activation in a mouse model of prostate cancer. We further show that rapamycin-induced MAPK activation occurs in both normal cells and cancer cells lines and that this feedback loop depends on an S6K-PI3K-Ras pathway. Significantly, pharmacological inhibition of the MAPK pathway enhanced the antitumoral effect of mTORC1 inhibition by rapamycin in cancer cells in vitro and in a xenograft mouse model. Taken together, our findings identify MAPK activation as a consequence of mTORC1 inhibition and underscore the potential of a combined therapeutic approach with mTORC1 and MAPK inhibitors, currently employed as single agents in the clinic, for the treatment of human cancers.

Uncompetitive NMDAR (N-methyl-D-aspartate receptor) antagonists restore impaired neural plasticity, reverse depressive-like behavior in animal models, and relieve major depressive disorder (MDD) in humans. This review integrates recent findings from in silico, in vitro, in vivo, and human studies of uncompetitive NMDAR antagonists into the extensive body of knowledge on NMDARs and neural plasticity. Uncompetitive NMDAR antagonists are activity-dependent channel blockers that preferentially target hyperactive GluN2D subtypes because these subtypes are most sensitive to activation by low concentrations of extracellular glutamate and are more likely activated by certain pathological agonists and allosteric modulators. Hyperactivity of GluN2D subtypes in specific neural circuits may underlie the pathophysiology of MDD. We hypothesize that neural plasticity is epigenetically regulated by precise Ca2+ quanta entering cells via NMDARs. Stimuli reach receptor cells (specialized cells that detect specific types of stimuli and convert them into electrical signals) and change their membrane potential, regulating glutamate release in the synaptic cleft. Free glutamate binds ionotropic glutamatergic receptors regulating NMDAR-mediated Ca2+ influx. Quanta of Ca2+ via NMDARs activate enzymatic pathways, epigenetically regulating synaptic protein homeostasis and synaptic receptor expression; thereby, Ca2+ quanta via NMDARs control the balance between long-term potentiation and long-term depression. This NMDAR Ca2+ quantal hypothesis for the epigenetic code of neural plasticity integrates recent psychopharmacology findings into established physiological and pathological mechanisms of brain function.

Pyruvate (PYR) dehydrogenase complex (PDC) is an enzymatic system that plays a crucial role in cellular metabolism as it controls the entry of carbon into the Krebs cycle. From a structural point of view, PDC is formed by three different subunits (E1, E2 and E3) capable of catalyzing the three reaction steps necessary for the full conversion of pyruvate to acetyl-CoA. Recent investigations pointed out the crucial role of this enzyme in the replication and survival of specific cancer cell lines, renewing the interest of the scientific community. Here, we report the results of our molecular dynamics studies on the mechanism by which posttranslational modifications, in particular the phosphorylation of three serine residues (Ser-264-α, Ser-271-α, and Ser-203-α), influence the enzymatic function of the protein. Our results support the hypothesis that the phosphorylation of Ser-264-α and Ser-271-α leads to (1) a perturbation of the catalytic site structure and dynamics and, especially in the case of Ser-264-α, to (2) a reduction in the affinity of E1 for the substrate. Additionally, an analysis of the channels connecting the external environment with the catalytic site indicates that the inhibitory effect should not be due to the occlusion of the access/egress pathways to/from the active site.

Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG upregulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation. Gene fusions involving the ERG transcription factor and point mutations in the ubiquitin ligase adaptor SPOP are two truncal mutations that are mutually exclusively present in prostate cancer. Here, the authors show that mutations in SPOP render prostate tumor cells sensitive to antiandrogen therapy and that the presence of ERG promotes sensitivity to high dose of androgen and SPOP inhibition.

Therapeutic resistance remains the principal barrier to durable clinical benefit in oncology, particularly in oncogene-driven malignancies and immune-refractory tumors. This meeting brought together leading experts to dissect the multifaceted biological mechanisms underlying drug tolerance, adaptive resistance, and immune escape across diverse cancer types. Presentations highlighted how cancer cell-intrinsic plasticity, chromatin reprogramming, and stress-responsive transcriptional networks intersect with tumor microenvironment-derived cues, including inflammatory signaling, stromal heterogeneity, mechanotransduction, and paracrine crosstalk, to sustain drug-tolerant persister states. Novel insights into cancer-associated fibroblast plasticity, spatially organized immunosuppressive niches, secretory autophagy, and senescence-associated programs underscored the dynamic and adaptive nature of resistance. Cutting-edge approaches, including single-cell and spatial transcriptomics, chromatin accessibility profiling, organoid-based co-culture platforms, and artificial intelligence-driven spatial inference, revealed actionable vulnerabilities and predictive biomarkers. Collectively, these studies emphasize that resistance is not a binary phenomenon but a continuum shaped by evolutionary adaptation and ecological interactions within the TME. This report synthesizes the conceptual advances and translational implications emerging from the meeting, outlining new therapeutic strategies aimed at disrupting adaptive tolerance states, reprogramming immunosuppressive niches, and enabling fast, accessible precision oncology.

Excessive Ca2+ currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders. Uncompetitive NMDAR channel blockers are an emerging class of drugs in clinical use for major depressive disorder (MDD) and other neuropsychiatric diseases. The pharmacological characterization of uncompetitive NMDAR blockers in clinical use may improve our understanding of NMDAR function in physiology and pathology. REL-1017 (esmethadone-HCl), a novel uncompetitive NMDAR channel blocker in Phase 3 trials for the treatment of MDD, was characterized together with dextromethorphan, memantine, (±)-ketamine, and MK-801 in cell lines over-expressing NMDAR subtypes using fluorometric imaging plate reader (FLIPR), automated patch-clamp, and manual patch-clamp electrophysiology. In the absence of Mg2+, NMDAR subtypes NR1-2D were most sensitive to low, sub-μM glutamate concentrations in FLIPR experiments. FLIPR Ca2+ determination demonstrated low μM affinity of REL-1017 at NMDARs with minimal subtype preference. In automated and manual patch-clamp electrophysiological experiments, REL-1017 exhibited preference for the NR1-2D NMDAR subtype in the presence of 1 mM Mg2+ and 1 μM L-glutamate. Tau off and trapping characteristics were similar for (±)-ketamine and REL-1017. Results of radioligand binding assays in rat cortical neurons correlated with the estimated affinities obtained in FLIPR assays and in automated and manual patch-clamp assays. In silico studies of NMDARs in closed and open conformation indicate that REL-1017 has a higher preference for docking and undocking the open-channel conformation compared to ketamine. In conclusion, the pharmacological characteristics of REL-1017 at NMDARs, including relatively low affinity at the NMDAR, NR1-2D subtype preference in the presence of 1 mM Mg2+, tau off and degree of trapping similar to (±)-ketamine, and preferential docking and undocking of the open NMDAR, could all be important variables for understanding the rapid-onset antidepressant effects of REL-1017 without psychotomimetic side effects.