Biology subjects

Kampen, K. R.

Publications and source records attributed to Kampen, K. R..

3 recordsLinked to original sources

bioRxiv2026

Sertraline and Carfilzomib Synergize to Target T-cell Malignancies with Serine/Glycine synthesis activity via Cholesterol Dysregulation, Cellular Stress and Immune Modulation

BackgroundT-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphoma (PTCL) are aggressive hematological malignancies requiring novel therapeutic strategies. The majority of T-ALL and PTCL tumors display metabolic activation and addiction to endogenous serine/glycine synthesis (SSP), providing opportunities for targeted therapy with the clinically used antidepressant sertraline, inhibiting SSP enzymes SHMT1/2. However, sertraline monotherapy only induces cell cycle arrest and has limited efficacy in suppressing disease progression in vivo. MethodsDrug synergy of sertraline combined with clinically used proteasome inhibitors carfilzomib and bortezomib was evaluated. Drug effects on cell cycle, proliferation and apoptosis were assessed in T-ALL, PTCL and healthy blood cells using flow cytometry assays. Proteomic, lipidomic and metabolic analyses on drug treated T-ALL cells were performed to elucidate the molecular mechanisms underlying drug synergy, followed by validation of changes of interest, metabolic rescues and shRNA-knockdown of SSP enzymes in T-ALL cells. In vivo therapeutic efficacy and immune remodelling were evaluated in an immunocompetent MYCN-overexpressing PTCL mouse model. ResultsSertraline acted synergistically with clinically used proteasome inhibitor carfilzomib to induce cell cycle arrest and apoptosis in T-ALL and PTCL cells with SSP activity, with minimal effects on SSP-inactive T-ALL cells or healthy blood cells. Adding carfilzomib also enhanced the therapeutic efficacy of sertraline in an aggressive MYCN PTCL model. Sertraline rewired cell metabolism towards increased cholesterol uptake and biosynthesis in SSP-active T-ALL cells, and this effect was not obtained by other means of SSP inhibition. In contrast to sertraline, carfilzomib promoted cholesterol efflux. Moreover, carfilzomib reduced total lipid levels, further restricting nutrients in sertraline - carfilzomib treated cells. Additionally, the drug combination impaired mitochondrial respiration and elevated reactive oxygen species (ROS) levels and DNA damage in SSP-active tumor cells, which was rescued by citrate supplementation. Interestingly, these metabolic changes were associated with microenvironmental changes in our mouse model, where the drug combination elevated natural killer T-cells, neutrophils and eosinophils. ConclusionsOur study identifies synergy of sertraline - carfilzomib combination treatment mediated through metabolic impairment and is associated with remodelling of the immune microenvironment. This invites for further clinical investigation of this drug combination as a therapeutic strategy for SSP-active T-cell malignancies.

cancer biology↗

bioRxiv2025

Adaptive Kinase Signaling Enables Escape from Small-Molecule Inhibition in Glioblastoma

Patients with glioblastoma (GB) have a median survival of 15 months. Despite an intensive treatment schedule with resection, radio- and chemotherapy, recurrence is inevitable. A significant challenge to overcome GB treatment resistance involves intratumoral heterogeneity, characterized by molecular, phenotypic, and clinical distinctive GB subtypes. Different small molecule inhibitors (SMI) have been designed to inhibit signalling proteins in oncogenic driver pathways in GB. However, SMIs have been unsuccessful in improving patient outcomes. Here, we investigate whether crosstalk between signalling pathways and signalling pathway redundancy are responsible for single-agent resistance using a primary patient-derived glioblastoma organoid (PGO) platform. This study used nine FDA-approved small-molecule inhibitors, based on their ability to cross the blood-brain barrier, targeting key GB driver genes. Although inhibition of downstream effector proteins reduced cell viability more effectively (IC50 70nM-1M) than inhibiting upstream membrane-bound tyrosine kinase receptors (IC50 1-15M), remaining cell proliferation was seen in all six PGOs. To uncover resistance mechanisms, we analysed phosphokinase activity following monotherapy in various PGOs and identified compensatory pathway activation, leading to the discovery of effective small-molecule inhibitor combinations, most notably CHIR99021 (GSK-3 inhibitor) with trametinib (MEK inhibitor). In conclusion, our findings highlight the potential of combination therapy targeting compensatory pathways to overcome single-agent resistance in GB, emphasizing the utility of patient-derived glioblastoma organoids as a platform for personalized therapeutic development.

cancer biology↗

bioRxiv2020

Repurposing the antidepressant sertraline as SHMT inhibitor to suppress serine/glycine synthesis addicted breast tumor growth.

Metabolic rewiring is a hallmark of cancer that supports tumor growth, survival and chemotherapy resistance. While normal cells often rely on extracellular serine and glycine supply, a significant subset of cancers becomes addicted to intracellular serine/glycine synthesis, offering an attractive drug target. Previously developed inhibitors of serine/glycine synthesis enzymes did not reach clinical trials due to unfavorable pharmacokinetic profiles, implying that further efforts to identify clinically applicable drugs targeting this pathway are required. In this study, we aimed to develop therapies that can rapidly enter the clinical practice by focusing on drug repurposing, as their safety and cost-effectiveness have been optimized before. Using a yeast model system, we repurposed two compounds, sertraline and thimerosal, for their selective toxicity against serine/glycine synthesis addicted breast cancer and T-cell acute lymphoblastic leukemia cell lines. Isotope tracer metabolomics, computational docking studies and an enzymatic activity assay revealed that sertraline and thimerosal inhibit serine/glycine synthesis enzymes serine hydroxymethyltransferase and phosphoglycerate dehydrogenase, respectively. In addition, we demonstrated that sertralines anti-proliferative activity was further aggravated by mitochondrial inhibitors, such as the antimalarial artemether, by causing G1-S cell cycle arrest. Most notably, this combination also resulted in serine-selective antitumor activity in breast cancer mouse xenografts. Collectively, this study provides molecular insights into the repurposed mode-of-action of the antidepressant sertraline and allows to delineate a hitherto unidentified group of cancers being particularly sensitive to treatment with sertraline. Furthermore, we highlight the simultaneous inhibition of serine/glycine synthesis and mitochondrial metabolism as a novel treatment strategy for serine/glycine synthesis addicted cancers.

cancer biology↗