MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis.

Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS-STING-mediated signalling and tumour suppression1-3. However, the precise mechanism of cGAS activation by endogenous DNA damage remains enigmatic, particularly given that high-affinity histone acidic patch (AP) binding constitutively inhibits cGAS by sterically hindering its activation by double-stranded DNA (dsDNA)4-10. Here we report that the DNA double-strand break sensor MRE11 suppresses mammary tumorigenesis through a pivotal role in regulating cGAS activation. We demonstrate that binding of the MRE11-RAD50-NBN complex to nucleosome fragments is necessary to displace cGAS from acidic-patch-mediated sequestration, which enables its mobilization and activation by dsDNA. MRE11 is therefore essential for cGAS activation in response to oncogenic stress, cytosolic dsDNA and ionizing radiation. Furthermore, MRE11-dependent cGAS activation promotes ZBP1-RIPK3-MLKL-mediated necroptosis, which is essential to suppress oncogenic proliferation and breast tumorigenesis. Notably, downregulation of ZBP1 in human triple-negative breast cancer is associated with increased genome instability, immune suppression and poor patient prognosis. These findings establish MRE11 as a crucial mediator that links DNA damage and cGAS activation, resulting in tumour suppression through ZBP1-dependent necroptosis.

Engineered Cas9 variants bypass Keap1-mediated degradation in human cells and enhance epigenome editing efficiency.

As a potent and convenient genome-editing tool, Cas9 has been widely used in biomedical research and evaluated in treating human diseases. Numerous engineered variants of Cas9, dCas9 and other related prokaryotic endonucleases have been identified. However, as these bacterial enzymes are not naturally present in mammalian cells, whether and how bacterial Cas9 proteins are recognized and regulated by mammalian hosts remain poorly understood. Here, we identify Keap1 as a mammalian endogenous E3 ligase that targets Cas9/dCas9/Fanzor for ubiquitination and degradation in an 'ETGE'-like degron-dependent manner. Cas9-'ETGE'-like degron mutants evading Keap1 recognition display enhanced gene editing ability in cells. dCas9-'ETGE'-like degron mutants exert extended protein half-life and protein retention on chromatin, leading to improved CRISPRa and CRISPRi efficacy. Moreover, Cas9 binding to Keap1 also impairs Keap1 function by competing with Keap1 substrates or binding partners for Keap1 binding, while engineered Cas9 mutants show less perturbation of Keap1 biology. Thus, our study reveals a mammalian specific Cas9 regulation and provides new Cas9 designs not only with enhanced gene regulatory capacity but also with minimal effects on disrupting endogenous Keap1 signaling.

cGAS/STING signalling pathway in senescence and oncogenesis.

The cGAS/STING signaling pathway is a crucial component of the innate immune system, playing significant roles in sensing cytosolic DNA, regulating cellular senescence, and contributing to oncogenesis. Recent advances have shed new lights into the molecular mechanisms governing pathway activation in multiple pathophysiological settings, the indispensable roles of cGAS/STING signaling in cellular senescence, and its context-dependent roles in cancer development and suppression. This review summarizes current knowledge related to the biology of cGAS/STING signaling pathway and its participations into senescence and oncogenesis. We further explore the clinical implications and therapeutic potential for cGAS/STING targeted therapies, and faced challenges in the field. With a focus on molecular mechanisms and emerging pharmacological targets, this review underscores the importance of future studies to harness the therapeutic potential of the cGAS/STING pathway in treating senescence-related disorders and cancer. Advanced understanding of the regulatory mechanisms of cGAS/STING signaling, along with the associated deregulations in diseases, combined with the development of new classes of cGAS/STING modulators, hold great promises for creating novel and effective therapeutic strategies. These advancements could address current treatment challenges and unlock the full potential of cGAS/STING in treating senescence-related disorders and oncogenesis.

Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt.

The retinoblastoma (Rb) protein exerts its tumor suppressor function primarily by inhibiting the E2F family of transcription factors that govern cell-cycle progression. However, it remains largely elusive whether the hyper-phosphorylated, non-E2F1-interacting form of Rb has any physiological role. Here we report that hyper-phosphorylated Rb directly binds to and suppresses the function of mTORC2 but not mTORC1. Mechanistically, Rb, but not p107 or p130, interacts with Sin1 and blocks the access of Akt to mTORC2, leading to attenuated Akt activation and increased sensitivity to chemotherapeutic drugs. As such, inhibition of Rb phosphorylation by depleting cyclin D or using CDK4/6 inhibitors releases Rb-mediated mTORC2 suppression. This, in turn, leads to elevated Akt activation to confer resistance to chemotherapeutic drugs in Rb-proficient cells, which can be attenuated with Akt inhibitors. Therefore, our work provides a molecular basis for the synergistic usage of CDK4/6 and Akt inhibitors in treating Rb-proficient cancer.

Development of VHL-recruiting STING PROTACs that suppress innate immunity.

STING acts as a cytosolic nucleotide sensor to trigger host defense upon viral or bacterial infection. While STING hyperactivation can exert anti-tumor effects by increasing T cell filtrates, in other contexts hyperactivation of STING can contribute to autoimmune and neuroinflammatory diseases. Several STING targeting agonists and a smaller subset of antagonists have been developed, yet STING targeted degraders, or PROTACs, remain largely underexplored. Here, we report a series of STING-agonist derived PROTACs that promote STING degradation in renal cell carcinoma (RCC) cells. We show that our STING PROTACs activate STING and target activated/phospho-STING for degradation. Locking STING on the endoplasmic reticulum via site-directed mutagenesis disables STING translocation to the proteasome and resultingly blocks STING degradation. We also demonstrate that PROTAC treatment blocks downstream innate immune signaling events and attenuates the anti-viral response. Interestingly, we find that VHL acts as a bona fide E3 ligase for STING in RCC; thus, VHL-recruiting STING PROTACs further promote VHL-dependent STING degradation. Our study reveals the design and biological assessment of VHL-recruiting agonist-derived STING PROTACs, as well as demonstrates an example of hijacking a physiological E3 ligase to enhance target protein degradation via distinct mechanisms.

Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer.

Cancer is the second leading cause of human death globally. PI3K/Akt/mTOR signaling is one of the most frequently dysregulated signaling pathways observed in cancer patients that plays crucial roles in promoting tumor initiation, progression and therapy responses. This is largely due to that PI3K/Akt/mTOR signaling is indispensable for many cellular biological processes, including cell growth, metastasis, survival, metabolism, and others. As such, small molecule inhibitors targeting major kinase components of the PI3K/Akt/mTOR signaling pathway have drawn extensive attention and been developed and evaluated in preclinical models and clinical trials. Targeting a single kinase component within this signaling usually causes growth arrest rather than apoptosis associated with toxicity-induced adverse effects in patients. Combination therapies including PI3K/Akt/mTOR inhibitors show improved patient response and clinical outcome, albeit developed resistance has been reported. In this review, we focus on revealing the mechanisms leading to the hyperactivation of PI3K/Akt/mTOR signaling in cancer and summarizing efforts for developing PI3K/Akt/mTOR inhibitors as either mono-therapy or combination therapy in different cancer settings. We hope that this review will facilitate further understanding of the regulatory mechanisms governing dysregulation of PI3K/Akt/mTOR oncogenic signaling in cancer and provide insights into possible future directions for targeted therapeutic regimen for cancer treatment, by developing new agents, drug delivery systems, or combination regimen to target the PI3K/Akt/mTOR signaling pathway. This information will also provide effective patient stratification strategy to improve the patient response and clinical outcome for cancer patients with deregulated PI3K/Akt/mTOR signaling.

TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling.

The mechanistic target of rapamycin (mTOR) has a key role in the integration of various physiological stimuli to regulate several cell growth and metabolic pathways. mTOR primarily functions as a catalytic subunit in two structurally related but functionally distinct multi-component kinase complexes, mTOR complex 1 (mTORC1) and mTORC2 (refs 1, 2). Dysregulation of mTOR signalling is associated with a variety of human diseases, including metabolic disorders and cancer. Thus, both mTORC1 and mTORC2 kinase activity is tightly controlled in cells. mTORC1 is activated by both nutrients and growth factors, whereas mTORC2 responds primarily to extracellular cues such as growth-factor-triggered activation of PI3K signalling. Although both mTOR and GßL (also known as MLST8) assemble into mTORC1 and mTORC2 (refs 11, 12, 13, 14, 15), it remains largely unclear what drives the dynamic assembly of these two functionally distinct complexes. Here we show, in humans and mice, that the K63-linked polyubiquitination status of GßL dictates the homeostasis of mTORC2 formation and activation. Mechanistically, the TRAF2 E3 ubiquitin ligase promotes K63-linked polyubiquitination of GßL, which disrupts its interaction with the unique mTORC2 component SIN1 (refs 12, 13, 14) to favour mTORC1 formation. By contrast, the OTUD7B deubiquitinase removes polyubiquitin chains from GßL to promote GßL interaction with SIN1, facilitating mTORC2 formation in response to various growth signals. Moreover, loss of critical ubiquitination residues in GßL, by either K305R/K313R mutations or a melanoma-associated GßL(ΔW297) truncation, leads to elevated mTORC2 formation, which facilitates tumorigenesis, in part by activating AKT oncogenic signalling. In support of a physiologically pivotal role for OTUD7B in the activation of mTORC2/AKT signalling, genetic deletion of Otud7b in mice suppresses Akt activation and Kras-driven lung tumorigenesis in vivo. Collectively, our study reveals a GßL-ubiquitination-dependent switch that fine-tunes the dynamic organization and activation of the mTORC2 kinase under both physiological and pathological conditions.

SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression.

The ERG gene is fused to TMPRSS2 in approximately 50% of prostate cancers (PrCa), resulting in its overexpression. However, whether this is the sole mechanism underlying ERG elevation in PrCa is currently unclear. Here we report that ERG ubiquitination and degradation are governed by the Cullin 3-based ubiquitin ligase SPOP and that deficiency in this pathway leads to aberrant elevation of the ERG oncoprotein. Specifically, we find that truncated ERG (ΔERG), encoded by the ERG fusion gene, is stabilized by evading SPOP-mediated destruction, whereas prostate cancer-associated SPOP mutants are also deficient in promoting ERG ubiquitination. Furthermore, we show that the SPOP/ERG interaction is modulated by CKI-mediated phosphorylation. Importantly, we demonstrate that DNA damage drugs, topoisomerase inhibitors, can trigger CKI activation to restore the SPOP/ΔERG interaction and its consequent degradation. Therefore, SPOP functions as a tumor suppressor to negatively regulate the stability of the ERG oncoprotein in prostate cancer.

Akt-mediated phosphorylation of XLF impairs non-homologous end-joining DNA repair.

Deficiency in repair of damaged DNA leads to genomic instability and is closely associated with tumorigenesis. Most DNA double-strand-breaks (DSBs) are repaired by two major mechanisms, homologous-recombination (HR) and non-homologous-end-joining (NHEJ). Although Akt has been reported to suppress HR, its role in NHEJ remains elusive. Here, we report that Akt phosphorylates XLF at Thr181 to trigger its dissociation from the DNA ligase IV/XRCC4 complex, and promotes its interaction with 14-3-3ß leading to XLF cytoplasmic retention, where cytosolic XLF is subsequently degraded by SCF(ß-TRCP) in a CKI-dependent manner. Physiologically, upon DNA damage, XLF-T181E expressing cells display impaired NHEJ and elevated cell death. Whereas a cancer-patient-derived XLF-R178Q mutant, deficient in XLF-T181 phosphorylation, exhibits an elevated tolerance of DNA damage. Together, our results reveal a pivotal role for Akt in suppressing NHEJ and highlight the tight connection between aberrant Akt hyper-activation and deficiency in timely DSB repair, leading to genomic instability and tumorigenesis.

Application of Copper(II)-Organic Frameworks Bearing Dilophine Derivatives in Photocatalysis and Guest Separation.

The functionalized design of metal-organic frameworks (MOFs) has been rapidly developed in the last 20 years, and its broad applicability has been demonstrated in many fields. MOFs with desired functions can be assembled using predesigned organic linkers with specific metal nodes, which possess the ordered functional sites and open structures. Although a large number of carboxylic acid junctions have been used to construct MOFs, it is still a great challenge to realize their multifunctionality. In particular, there is a relative lack of research on MOFs as direct photocatalysts, which require not only abundant active sites and open structures but also adsorption groups and effective electron-hole separation performance. To this end, MOFs constructed from the carboxylic acid ligands derived from lophine-based derivatives and copper ions were deliberately used as a photocatalyst, and then, their application in dye degradation and aromatic alcohol conversion was investigated. In addition, in combination with the abundant Lewis sites of copper ions and imidazole sites, the material shows not only the adsorption and separation of C2 series and dyes but also the application of dye degradation and conversion of aromatic alcohols under illumination conditions. The corresponding results fully illustrate that the MOF constructed by using lophine derivatives can be an effective way to prepare photocatalysts. The subsequent research ideas will focus on designing a series of MOFs constructed with multilinked moieties of lophine groups and exploring their application strategies in the field of photocatalysis.

Roles of Ubiquitination and SUMOylation in DNA Damage Response.

Ubiquitin and ubiquitin-like modifiers, such as SUMO, exert distinct physiological functions by conjugating to protein substrates. Ubiquitination or SUMOylation of protein substrates determine the fate of modified proteins, including proteasomal degradation, cellular re-localization, alternations in binding partners and serving as a protein-binding platform, in a ubiquitin or SUMO linkage-dependent manner. DNA damage occurs constantly in living organisms but is also repaired by distinct tightly controlled mechanisms including homologous recombination, non-homologous end joining, inter-strand crosslink repair, nucleotide excision repair and base excision repair. On sensing damaged DNA, a ubiquitination/SUMOylation landscape is established to recruit DNA damage repair factors. Meanwhile, misloaded and mission-completed repair factors will be turned over by ubiquitin or SUMO modifications as well. These ubiquitination and SUMOylation events are tightly controlled by both E3 ubiquitin/SUMO ligases and deubiquitinases/deSUMOylases. In this review, we will summarize identified ubiquitin and SUMO-related modifications and their function in distinct DNA damage repair pathways, and provide evidence for responsible E3 ligases, deubiquitinases, SUMOylases and deSUMOylases in these processes. Given that genome instability leads to human disorders including cancer, understanding detailed molecular mechanisms for ubiquitin and SUMO-related regulations in DNA damage response may provide novel insights into therapeutic modalities to treat human diseases associated with deregulated DNA damage response.

Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus.

Akt, also known as protein kinase B, plays key roles in cell proliferation, survival and metabolism. Akt hyperactivation contributes to many pathophysiological conditions, including human cancers, and is closely associated with poor prognosis and chemo- or radiotherapeutic resistance. Phosphorylation of Akt at S473 (ref. 5) and T308 (ref. 6) activates Akt. However, it remains unclear whether further mechanisms account for full Akt activation, and whether Akt hyperactivation is linked to misregulated cell cycle progression, another cancer hallmark. Here we report that Akt activity fluctuates across the cell cycle, mirroring cyclin A expression. Mechanistically, phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation. Furthermore, deletion of the cyclin A2 allele in the mouse olfactory bulb leads to reduced S477/T479 phosphorylation and elevated cellular apoptosis. Notably, cyclin A2-deletion-induced cellular apoptosis in mouse embryonic stem cells is partly rescued by S477D/T479E-Akt1, supporting a physiological role for cyclin A2 in governing Akt activation. Together, the results of our study show Akt S477/T479 phosphorylation to be an essential layer of the Akt activation mechanism to regulate its physiological functions, thereby providing a new mechanistic link between aberrant cell cycle progression and Akt hyperactivation in cancer.

mTOR drives its own activation via SCF(ßTrCP)-dependent degradation of the mTOR inhibitor DEPTOR.

The activities of both mTORC1 and mTORC2 are negatively regulated by their endogenous inhibitor, DEPTOR. As such, the abundance of DEPTOR is a critical determinant in the activity status of the mTOR network. DEPTOR stability is governed by the 26S-proteasome through a largely unknown mechanism. Here we describe an mTOR-dependent phosphorylation-driven pathway for DEPTOR destruction via SCF(ßTrCP). DEPTOR phosphorylation by mTOR in response to growth signals, and in collaboration with casein kinase I (CKI), generates a phosphodegron that binds ßTrCP. Failure to degrade DEPTOR through either degron mutation or ßTrCP depletion leads to reduced mTOR activity, reduced S6 kinase activity, and activation of autophagy to reduce cell growth. This work expands the current understanding of mTOR regulation by revealing a positive feedback loop involving mTOR and CKI-dependent turnover of its inhibitor, DEPTOR, suggesting that misregulation of the DEPTOR destruction pathway might contribute to aberrant activation of mTOR in disease.

CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1.

Drosophila contains one (dCDK12) and humans contain two (hCDK12 and hCDK13) proteins that are the closest evolutionary relatives of yeast Ctk1, the catalytic subunit of the major elongation-phase C-terminal repeat domain (CTD) kinase in Saccharomyces cerevisiae, CTDK-I. However, until now, neither CDK12 nor CDK13 has been demonstrated to be a bona fide CTD kinase. Using Drosophila, we demonstrate that dCDK12 (CG7597) is a transcription-associated CTD kinase, the ortholog of yCtk1. Fluorescence microscopy reveals that the distribution of dCDK12 on formaldehyde-fixed polytene chromosomes is virtually identical to that of hyperphosphorylated RNA polymerase II (RNAPII), but is distinct from that of P-TEFb (dCDK9 + dCyclin T). Chromatin immunoprecipitation (ChIP) experiments confirm that dCDK12 is present on the transcribed regions of active Drosophila genes. Compared with P-TEFb, dCDK12 amounts are lower at the 5' end and higher in the middle and at the 3' end of genes (both normalized to RNAPII). Appropriately, Drosophila dCDK12 purified from nuclear extracts manifests CTD kinase activity in vitro. Intriguingly, we find that cyclin K is associated with purified dCDK12, implicating it as the cyclin subunit of this CTD kinase. Most importantly, we demonstrate that RNAi knockdown of dCDK12 in S2 cells alters the phosphorylation state of the CTD, reducing its Ser2 phosphorylation levels. Similarly, in human HeLa cells, we show that hCDK13 purified from nuclear extracts displays CTD kinase activity in vitro, as anticipated. Also, we find that chimeric (yeast/human) versions of Ctk1 containing the kinase homology domains of hCDK12/13 (or hCDK9) are functional in yeast cells (and also in vitro); using this system, we show that a bur1(ts) mutant is rescued more efficiently by a hCDK9 chimera than by a hCDK13 chimera, suggesting the following orthology relationships: Bur1 ↔ CDK9 and Ctk1 ↔ CDK12/13. Finally, we show that siRNA knockdown of hCDK12 in HeLa cells results in alterations in the CTD phosphorylation state. Our findings demonstrate that metazoan CDK12 and CDK13 are CTD kinases, and that CDK12 is orthologous to yeast Ctk1.

mTOR signaling in tumorigenesis.

mTOR (the mechanistic target of rapamycin) is an atypical serine/threonine kinase involved in regulating major cellular functions including growth and proliferation. Deregulation of the mTOR signaling pathway is one of the most commonly observed pathological alterations in human cancers. To this end, oncogenic activation of the mTOR signaling pathway contributes to cancer cell growth, proliferation and survival, highlighting the potential for targeting the oncogenic mTOR pathway members as an effective anti-cancer strategy. In order to do so, a thorough understanding of the physiological roles of key mTOR signaling pathway components and upstream regulators would guide future targeted therapies. Thus, in this review, we summarize available genetic mouse models for mTORC1 and mTORC2 components, as well as characterized mTOR upstream regulators and downstream targets, and assign a potential oncogenic or tumor suppressive role for each evaluated molecule. Together, our work will not only facilitate the current understanding of mTOR biology and possible future research directions, but more importantly, provide a molecular basis for targeted therapies aiming at key oncogenic members along the mTOR signaling pathway.

Therapeutic Implications for Overcoming Radiation Resistance in Cancer Therapy.

Ionizing radiation (IR), such as X-rays and gamma (γ)-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability contribute to IR-induced cancer cell death. Although IR therapy may be curative in a number of cancer types, the resistance of cancer cells to radiation remains a major therapeutic problem. In this review, we describe the morphological and molecular aspects of various IR-induced types of cell death. We also discuss cytogenetic variations representative of IR-induced DNA damage and genomic instability. Most importantly, we focus on several pathways and their associated marker proteins responsible for cancer resistance and its therapeutic implications in terms of cancer cell death of various types and characteristics. Finally, we propose radiation-sensitization strategies, such as the modification of fractionation, inflammation, and hypoxia and the combined treatment, that can counteract the resistance of tumors to IR.

Dynamic Event-Triggered Safe Control for Nonlinear Game Systems With Asymmetric Input Saturation.

This article focuses on the Pareto optimal issues of nonlinear game systems with asymmetric input saturation under dynamic event-triggered mechanism (DETM). First, the safe control is guaranteed by transforming the system with safety constraints into the one without state constraints utilizing barrier function. The united cost function integrating nonquadratic utility function is constructed to provide the foundation to achieve the Pareto optimal solutions. Then, the adaptive dynamic programming method with concurrent learning is proposed to approximate the Pareto optimal strategies wherein both current and historical data are utilized. To further lessen the consumptions of computation/communication resources, the DETM is integrated into the adaptive algorithm framework which can avoid Zeno phenomena. All the signals of the closed-loop system are proved to be uniformly ultimately bounded. Finally, the simulation results are given to validate the effectiveness of the proposed method from several aspects.

Introducing a Pyrazinoquinoxaline Derivative into a Metal-Organic Framework: Achieving Fluorescence-Enhanced Detection for Cs+ and Enhancing Photocatalytic Activity.

Conventional photoresponsive materials have low photon utilization due to irregular distribution of photoactive groups, which severely limits the related real applications. Metal-organic frameworks (MOFs) can modulate the regular arrangement of functional groups to improve the electron transport paths and enhance the photon utilization, which provides strong support for the development of photoactive materials with excellent performance. In this work, one effective strategy for constructing a photoactive MOF had been developed via the utilization of Cd2+ and pyrazinoquinoxaline tetracarboxylic acid. The structural advantages of the Cd-MOF, such as a porous structure, abundant subject-object interaction sites, and a stable framework, ensure the prerequisite for various applications, while the better synergistic effect of Cd3 clusters and the pyrazinoquinoxaline derivative ensures efficient electron transfer efficiency. Therefore, by virtue of these structural advantages, the Cd-MOF can achieve fluorescence quenching detection for a variety of substrates, such as Fe3+, Cr2O72-, MnO4-, nitrofuran antibiotics, and TNP explosives, while fluorescence enhancement detection can be achieved for halogen ions, Cs+, Pb2+, and NO2-. In addition, the Cd-MOF can be used as a photocatalyst to successfully achieve the photocatalytic conversion of benzylamine to N-benzylbenzimidate under mild conditions. Thus, the Cd-MOF as a whole shows the possibility of application as a diverse fluorescence detection and photocatalyst and also illustrates the feasibility of preparing high-performance photoactive materials using the pyrazinoquinoxaline derivative.

Co-targeting JAK1/STAT6/GAS6/TAM signaling improves chemotherapy efficacy in Ewing sarcoma.

Ewing sarcoma is a pediatric bone and soft tissue tumor treated with chemotherapy, radiation, and surgery. Despite intensive multimodality therapy, ~50% patients eventually relapse and die of the disease due to chemoresistance. Here, using phospho-profiling, we find Ewing sarcoma cells treated with chemotherapeutic agents activate TAM (TYRO3, AXL, MERTK) kinases to augment Akt and ERK signaling facilitating chemoresistance. Mechanistically, chemotherapy-induced JAK1-SQ phosphorylation releases JAK1 pseudokinase domain inhibition allowing for JAK1 activation. This alternative JAK1 activation mechanism leads to STAT6 nuclear translocation triggering transcription and secretion of the TAM kinase ligand GAS6 with autocrine/paracrine consequences. Importantly, pharmacological inhibition of either JAK1 by filgotinib or TAM kinases by UNC2025 sensitizes Ewing sarcoma to chemotherapy in vitro and in vivo. Excitingly, the TAM kinase inhibitor MRX-2843 currently in human clinical trials to treat AML and advanced solid tumors, enhances chemotherapy efficacy to further suppress Ewing sarcoma tumor growth in vivo. Our findings reveal an Ewing sarcoma chemoresistance mechanism with an immediate translational value.

Skp2: a novel potential therapeutic target for prostate cancer.

Prostate cancer is the most frequently diagnosed tumor in men and the second most common cause of cancer-related death for males in the United States. It has been shown that multiple signaling pathways are involved in the pathogenesis of prostate cancer, such as androgen receptor (AR), Akt, Wnt, Hedgehog (Hh) and Notch. Recently, burgeoning amounts of evidence have implicated that the F-box protein Skp2 (S-phase kinase associated protein 2), a well-characterized oncoprotein, also plays a critical role in the development and progression of prostate cancer. Therefore, this review discusses the recent literature regarding the function and regulation of Skp2 in the pathogenesis of prostate cancer. Furthermore, we highlight that Skp2 may represent an attractive therapeutic target, thus warrants further development of agents to target Skp2, which could have significant therapeutic impact on prostate cancer.