Biology subjects

Zhang, Y.-Q.

Publications and source records attributed to Zhang, Y.-Q..

7 recordsLinked to original sources

bioRxiv2026

Dual targeting of PDPK1 and BRAF V600E is synthetically lethal

PDPK1 functions downstream of PI3K and is essential for activating AKT and other AGC kinases. Although PDPK1 has a central role in the PI3K/AKT/mTOR signaling pathway, there has been limited evaluation of it as a target for cancer therapy. Anaplastic thyroid cancer (ATC) has one of the highest mortality rates of all human malignancies. Although combined BRAF and MEK inhibition in BRAF V600E mutant ATC (present in 45% of cases) results in response, resistance is common, and there is no curative treatment for ATC. The majority (up to 95.8%) of ATC cases have activation in the PI3K/AKT/mTOR and RAS/RAF/MEK/MAPK pathways due to genetic alterations involved in these pathways. In this study, we investigated PDPK1 as a therapeutic target for ATC. We used in vitro, ex vivo, and in vivo ATC models to evaluate the effect of targeting PDPK1 (BX795) alone and in combination with BRAF V600E inhibition (dabrafenib), and the mechanism of action that resulted in ATC cell death. BX795 monotherapy significantly reduced ATC cell proliferation, invasion, colony formation, and spheroid size. Combination BX795 and dabrafenib treatment had strong synergistic anticancer activity in BRAF V600E-mutant ATC models and led to simultaneous and sustained suppression of PDPK1/AKT and MAPK signaling, preventing the compensatory pathway reactivation observed with single-agent treatment. Mechanistically, combined inhibition induced pronounced oxidative stress, DNA damage, and G2-phase cell-cycle arrest, accompanied by mitochondrial dysfunction and robust activation of apoptosis in ATC cells. These effects resulted in marked tumor regression in in vitro, ex vivo, and in vivo ATC models. Our findings identify PDPK1 as a critical therapeutic vulnerability in ATC. Co-targeting PDPK1 and BRAF V600E produces potent synergistic anticancer activity by shutting down convergent oncogenic signaling pathways and amplifying apoptotic stress responses. These data support PDPK1 inhibition alone and in combination with BRAF blockade as a promising therapeutic strategy in BRAF V600E-mutant cancers.

cancer biology↗

bioRxiv2024

A novel combination of CDK4/6 and PI3K inhibitors exhibits highly synergistic activity and translational potential in Ewing sarcoma.

Ewing sarcoma is a highly aggressive solid malignancy affecting children and young adults. Ewing sarcoma is driven primarily by EWSR1::FLI1, a fusion oncoprotein that has been notoriously difficult to target with traditional pharmacologic agents. There are numerous examples of preclinical promising combinations of small molecules that are never tested in pediatric clinical trials because agents fail to reach the market due to limited efficacy for common adult cancers. Moreover, the effectiveness of single-agent therapies for cancer treatment is often limited. To address these limitations, we selected 28 compounds that were largely FDA approved or in late stages of clinical development and known to regulate important pathways in Ewing sarcoma. We performed a drug screen in Ewing sarcoma cell lines with 180 combinations of tyrosine kinase inhibitors, cell cycle inhibitors, and conventional chemotherapy. The results of the screen revealed that a PI3K inhibitor, copanlisib, combined with a CDK4/6 inhibitor, ribociclib, exhibited strong synergistic anti-Ewing sarcoma activity. Using proteomic methods such as a reverse-phase protein array and western immunoblotting, we demonstrated that this combination induced a downregulation of the PI3K/AKT pathway as well as proteins involved in cell cycle regulation. We further confirmed these in vitro data using bulk RNA-sequencing. To evaluate the phenotypic effect of the PI3K/CDK4/6 inhibition in Ewing sarcoma lines, we performed apoptosis and cell cycle analyses using flow cytometry and demonstrated that ribociclib primarily induced a G0/G1 arrest with minimal effect on Ewing cell viability but significantly enhanced the apoptotic effect of copanlisib treatment. In a xenograft model of Ewing sarcoma, we demonstrated that the combination therapy significantly prolonged survival compared to treatment with either vehicle or single-agent therapy alone. Our findings identify a new candidate therapy combination for Ewing sarcoma using FDA-approved drugs and provide a resource of additional potential synergistic combinations for future validation. Statement of translational relevanceTreatment of patients with newly diagnosed Ewing sarcoma involves intensive multi- agent chemotherapy, radiation, and surgery, often leading to long-term toxicities. Children with relapsed or metastatic disease experience poor outcomes with five-year overall survival rates of only 15 to 30 percent. Therefore, new therapeutic approaches are urgently needed. Our drug screen revealed several promising combinations with synergistic anti-Ewing sarcoma activity including the PI3K inhibitor copanlisib with the CDK4/6 inhibitor ribociclib. This combination also significantly improved survival in a mouse xenograft model of Ewing sarcoma compared to treatment with vehicle or either drug alone. Pre-clinical validation of a combination therapy composed of two FDA- approved drugs nominates this combination for early phase trials for patients with with relapsed or refractory Ewing sarcoma, a group of patients greatly in need of new therapeutic opportunities. The data generated by our drug screen may also be used as a resource to identify other promising combinations for future validation as Ewing sarcoma therapies.

cancer biology↗

bioRxiv2024

Pexidartinib plus FLT3-directed CAR-Macrophage for the treatment of FLT3-ITD-mutated acute myeloid leukemia in preclinical model

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) mutations occur in about 25%-30% of AML cases and are associated with adverse prognosis. Recent advances indicate that M2-like leukemia-associated macrophages (M2-LAM) are highly infiltrated in the bone marrow of FLT3-ITD+ AML patients; however, the underlying mechanisms and therapeutic implications are still elusive. Herein, we reveal that conditioned medium from FLT3-ITD+ MOLM-13 AML cells polarized M2-LAM and impaired their phagocytic activities. Unexpectedly, co-culture of M2-LAM protected MOLM-13 cells from the treatment of FLT3 inhibitor quizartinib by activating their FLT3 signaling pathway. Pharmaceutically, FLT3/CSF1R dual inhibitor pexidartinb effectively suppressed M2-LAM, reduced leukemic burden, and prolonged the survival of MOLM-13-xenografted mice. To enhance the phagocytic activities of macrophages, FLT3-directed chimeric antigen receptor-engineered macrophages (FLT3L-CAR-Macrophage) were generated using FLT3 ligand (FLT3L) as the recognizing domain of CAR. Transfection of THP-1 monocytic cells-or umbilical cord blood mononuclear cells-derived macrophages with FLT3L-CAR-encoding mRNA enhanced their phagocytic activities to MOLM-13 cells in vitro. Consistently, FLT3L-CAR-Macrophage differentiated from FLT3L-CAR-expressing THP-1 cells effectively phagocytosed MOLM-13 cells in vitro, reduced leukemic burden and prolonged the survival of MOLM-13-xenografted mice. Importantly, treatment of pexidartinib resulted in upregulation and surface localization of FLT3-ITD protein in MOLM-13 cells, sensitized MOLM-13 cells to the treatment of FLT3L-CAR-Macrophage in vitro, and synergized with FLT3L-CAR-Macrophage to further reduce leukemic burden in MOLM-13-xenografted mice. Together, our data indicate that pexidartinib plus FLT3L-CAR-Macrophage could be a promising therapeutic strategy for the treatment of FLT3-ITD+ AML in preclinical model which warrants further investigation. Graphical AbstractPexidartinib plus FLT3L-CAR-M{varphi} for the treatment of FLT3-ITD+ AML in preclinical model. Pexidartinib suppressed AML growth, reduced M2-LAM, increased FLT3 surface expression and synergized with FLT3L-CAR-M{varphi} to target FLT3-ITD+ AML in vitro and in vivo. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/615313v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1e7c0f4org.highwire.dtl.DTLVardef@2cdf6eorg.highwire.dtl.DTLVardef@e84borg.highwire.dtl.DTLVardef@1929d28_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

A comprehensive collection of pain and addiction targets and compounds library for high throughput screening and AI-driven drug discovery

As part of the NIH Helping to End Addiction Long-term (HEAL) Initiative, the National Center for Advancing Translational Sciences (NCATS) is dedicated to the development of new pharmacological tools and investigational drugs for managing and treating pain, as well as the prevention and treatment of opioid misuse and addiction. In line with these objectives, we created a comprehensive, annotated small molecule library including drugs, probes, and tool compounds that act on published pain and addiction-relevant targets. Nearly 3,000 small molecules associated with approximately 200 known and hypothesized HEAL targets have been assembled, curated, and annotated in one collection. Physical samples of the library compounds have been acquired and plated in 1536-well format, enabling rapid and efficient high throughput screen (HTS) against a wide range of assays. The creation of the HEAL Targets and Compounds Library, coupled with an integrated computational platform for AI-driven machine learning (ML), structural modeling, and virtual screening (VS), provides a valuable source for strategic drug repurposing, innovative profiling, and hypothesis testing of novel targets related to pain and opioid use disorder (OUD). The library is available to investigators for screening pain and OUD-relevant phenotypes.

bioinformatics↗

bioRxiv2022

Asymmetric activation of microglia in the hippocampus drives anxiodepressive consequences of trigeminal neuralgia

Patients suffering from trigeminal neuralgia (TN) are often accompanied by anxiety and depression. Whether and how microglia are involved in TN-induced anxiodepressive remains unclear. Here, we unconventionally report that TN activates ipsilateral but not contralateral hippocampal microglia, upregulates ipsilateral hippocampal ATP and interleukin1{beta} (IL-1{beta}) levels, impairs ipsilateral hippocampal long-term potentiation (LTP), and induces anxiodepressive-like behaviors in a time-dependent manner in rodents. Specifically, activation of ipsilateral hippocampal microglia is necessary for TN-induced anxiodepressive-like behaviors; and unilateral activating hippocampal microglia is sufficient to elicit an anxiodepressive state and impair LTP. Knockdown of ipsilateral hippocampal P2X7 receptor prevented TN-induced microglial activation and anxiodepressive-like behaviors. Furthermore, we demonstrate that microglia-derived IL-1{beta} mediates microglial activation-induced anxiodepressive-like behaviors and LTP impairment. Together, these findings suggest that priming of microglia with ATP/P2X7R in the ipsilateral hippocampus drives pain-related anxiodepressive-like behaviors via IL-1{beta}. Our results also reveal an asymmetric role of the bilateral hippocampus in TN-induced anxiety and depression.

neuroscience↗

bioRxiv2021

Photosynthetic induction upon transfer from low to high light is affected by leaf nitrogen content in tomato

The response of photosynthetic CO2 assimilation to changes of illumination affects plant growth and crop productivity under natural fluctuating light conditions. However, the effects of nitrogen (N) supply on photosynthetic physiology after transition from low to high light are seldom studied. To elucidate this, we measured gas exchange and chlorophyll fluorescence under fluctuating light in tomato (Solanum lycopersicum) seedlings grown with different N conditions. After transition from low to high light, the induction speeds of net CO2 assimilation (AN), stomatal conductance (gs) and mesophyll conductance (gm) delayed with the decline in leaf N content. The times to reach 90% of maximum AN, gs and gm were negatively correlated to leaf N content. This delayed photosynthetic induction in plants grown under low N concentration was mainly caused by the slow induction response of gm rather than that of gs. Furthermore, the photosynthetic induction upon transfer from low to high light was hardly limited by photosynthetic electron flow. These results indicate that decreased leaf N content declines carbon gain under fluctuating light in tomato. Increasing the induction kinetics of gm has the potential to enhance the carbon gain of field crops grown in infertile soil.

plant biology↗

bioRxiv2018

Interleukin-17 regulates neuron-glial communications, inhibitory synaptic transmission and neuropathic pain after chemotherapy

The proinflammatory cytokine Interleukin-17 (IL-17) is produced mainly by Th17 cells and has been implicated in pain regulation. However, synaptic mechanisms by which IL-17 regulates pain transmission are unknown. Here we report that glia-produced IL-17 suppresses inhibitory synaptic transmission in spinal cord pain circuit and drives chemotherapy-induced neuropathic pain. We observed respective expression of IL-17 and its receptor IL-17R in spinal cord astrocytes and neurons. Patch clamp recording in spinal cord slices revealed that IL-17 not only enhanced EPSCs but also suppressed IPSCs and GABA-induced currents in lamina IIo somatostatin-expressing neurons. Spinal IL-17 was upregulated after paclitaxel treatment, and intrathecal IL-17R blockade reduced paclitaxel-induced neuropathic pain. In dorsal root ganglia, respective IL-17 and IL-17R expression in satellite glial cells and neurons was sufficient and required for inducing neuronal hyperexcitability after paclitaxel. Together, our data show that IL-17/IL-17R mediate both central and peripheral neuron-glial interactions in chemotherapy-induced peripheral neuropathy.

neuroscience↗