Altered mitochondrial dynamics can broadly impact tumor cell physiology. Using genetic and pharmacological profiling of cancer cell lines and human tumors, we here establish that perturbations to the mitochondrial dynamics network also result in specific therapeutic vulnerabilities. In particular, through distinct mechanisms, tumors with increased mitochondrial fragmentation or connectivity are hypersensitive to SMAC mimetics, a class of compounds that induce apoptosis through inhibition of IAPs and for which robust sensitivity biomarkers remain to be identified. Further, because driver oncogenes exert dominant control over mitochondrial dynamics, oncogene-targeted therapies can be used to sensitize tumors to SMAC mimetics via their effects on fission/fusion dynamics. Collectively, these data demonstrate that perturbations to the mitochondrial dynamics network induce targetable vulnerabilities across diverse human tumors and, more broadly, suggest that the altered structures, activities, and trafficking of cellular organelles may facilitate additional cancer therapeutic opportunities.
PARP inhibitors (PARPi) have been effective in high-grade serous ovarian cancer (HGSOC), although clinical activity is limited against BRCA wild type HGSOC. The nearly universal loss of normal p53 regulation in HGSOCs causes dysfunction in the G1/S checkpoint, making tumor cells reliant on Chk1-mediated G2/M cell cycle arrest for DNA repair. Therefore, Chk1 is a reasonable target for a combination strategy with PARPi in treating BRCA wild type HGSOC. Here we investigated the combination of prexasertib mesylate monohydrate (LY2606368), a Chk1 and Chk2 inhibitor, and a PARP inhibitor, olaparib, in HGSOC cell lines (OVCAR3, OV90, PEO1 and PEO4) using clinically attainable concentrations. Our findings showed combination treatment synergistically decreased cell viability in all cell lines and induced greater DNA damage and apoptosis than the control and/or monotherapies (p<0.05). Treatment with olaparib in BRCA wild type HGSOC cells caused formation of Rad51 foci, whereas the combination treatment with prexasertib inhibited transnuclear localization of Rad51, a key protein in homologous recombination repair. Overall, our data provide evidence that prexasertib and olaparib combination resulted in synergistic cytotoxic effects against BRCA wild type HGSOC cells through reduced Rad51 foci formation and greater induction of apoptosis. This may be a novel therapeutic strategy for HGSOC.
Using metabolically focused CRISPR/ Cas9 loss-of-function screens, Lin and Xie et al. map the metabolic-apoptotic interface in AML, revealing metabolic pathways that can be therapeutically targeted to augment chemotherapy. In particular, the authors identify heme biosynthesis as an actionable pathway whose prognostic importance is supported by clinical omics data.
Short circulation time and off‐target toxicity are the main challenges faced by small‐molecule chemotherapeutics. To overcome these shortcomings, an albumin‐binding peptide conjugate of chemotherapeutics is developed that binds specifically to endogenous albumin and harnesses its favorable pharmacokinetics and pharmacodynamics for drug delivery to tumors. A protein‐G‐derived albumin‐binding domain (ABD) is conjugated with doxorubicin (Dox) via a pH‐sensitive linker. One to two Dox molecules are conjugated to ABD without loss of aqueous solubility. The albumin‐binding ABD–Dox conjugate exhibits nanomolar affinity for human and mouse albumin, and upon administration in mice, shows a plasma half‐life of 29.4 h, which is close to that of mouse albumin. Additionally, 2 h after administration, ABD–Dox exhibits an approximately 4‐fold higher concentration in the tumor than free Dox. Free Dox clears quickly from the tumor, while ABD–Dox maintains a steady concentration in the tumor for at least 72 h, so that its relative accumulation at 72 h is ≈120‐fold greater than that of free Dox. The improved pharmacokinetics and biodistribution of ABD–Dox result in enhanced therapeutic efficacy in syngeneic C26 colon carcinoma and MIA PaCa‐2 pancreatic tumor xenografts, compared with free Dox and aldoxorubicin, an albumin‐reactive Dox prodrug currently in clinical development.
We report the development of drug-encapsulating nanoparticles that bind endogenous albumin upon intravenous injection and evaluate their in vivo performance in a murine as well as canine animal model. The gene encoding a protein-G derived albumin binding domain (ABD) was fused to that of a chimeric polypeptide (CP), and the ABD-CP fusion was recombinantly synthesized by bacterial expression of the gene. Doxorubicin (DOX) was conjugated to the C-terminus of the ABD-CP fusion, and conjugation of multiple copies of the drug to one end of the ABD-CP triggered its self-assembly into ∼100 nm diameter spherical micelles. ABD-decorated micelles exhibited submicromolar binding affinity for albumin and also preserved their spherical morphology in the presence of albumin. In a murine model, albumin-binding micelles exhibited dose-independent pharmacokinetics, whereas naked micelles exhibited dose-dependent pharmacokinetics. In addition, in a canine model, albumin binding micelles resulted in a 3-fold increase in plasma half-life and 6-fold increase in plasma exposure as defined by the area under the curve (AUC) of the drug, compared with naked micelles. Furthermore, in a murine colon carcinoma model, albumin-binding nanoparticles demonstrated lower uptake by the reticuloendothelial system (RES) system organs, the liver and spleen, that are the main target organs of toxicity for nanoparticulate delivery systems and higher uptake by the tumor than naked micelles. The increased uptake by s.c. C26 colon carcinoma tumors in mice translated to a wider therapeutic window of doses ranging from 20 to 60 mg equivalent of DOX per kg body weight (mg DOX equiv•kg −1 BW) for albumin-binding ABD-CP-DOX micelles, as compared to naked micelles that were only effective at their maximum tolerated dose of 40 mg DOX equiv•kg −1 BW.
ACTL6B is a component of the neuronal BRG1/brm‐associated factor (nBAF) complex, which is required for chromatin remodeling in postmitotic neurons. We recently reported biallelic pathogenic variants in ACTL6B in patients diagnosed with early infantile epileptic encephalopathy, subtype 76 (EIEE‐76), presenting with severe, global developmental delay, epileptic encephalopathy, cerebral atrophy, and abnormal central nervous system myelination. However, the pathophysiological mechanisms underlying their phenotype is unknown. Here, we investigate the molecular pathogenesis of ACTL6B p.(Val421_Cys425del) using in silico 3D protein modeling predictions and patient‐specific induced pluripotent stem cell‐derived neurons. We found neurons derived from EIEE‐76 patients showed impaired accumulation of ACTL6B compared to unaffected relatives, caused by reduced protein stability. Furthermore, EIEE‐76 patient‐derived neurons had dysregulated nBAF target gene expression, including genes important for neuronal development and disease. Multielectrode array system analysis unveiled elevated electrophysiological activity of EIEE‐76 patients‐derived neurons, consistent with the patient phenotype. Taken together, our findings validate a new model for EIEE‐76 and reveal how reduced ACTL6B expression affects neuronal function.
Recent advances in genetic diagnosis identified variants in genes encoding GABAA receptors as causative for genetic epilepsy. Here, we selected eight disease-associated variants in the alpha1 subunit of GABAA receptors causing mild to severe clinical phenotypes and showed that they are loss of function, mainly by reducing the folding and surface trafficking of the alpha1 protein. Furthermore, we sought client protein-specific pharmacological chaperones to restore the function of pathogenic receptors. Applications of positive allosteric modulators, including Hispidulin and TP003, increase the functional surface expression of the alpha1 variants. Mechanism of action study demonstrated that they enhance the folding and assembly and reduce the degradation of GABAA variants without activating the unfolded protein response in HEK293T cells and human iPSC-derived neurons. Since these compounds cross the blood-brain barrier, such a pharmacological chaperoning strategy holds great promise to treat genetic epilepsy in a GABAA receptor-specific manner.
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