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MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE162681 | GEO | 2020/12/05

REPOSITORIES: GEO

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<i>MYCN</i> drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity.

Project description:Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by initial chemosensitivity followed by emergence of chemoresistant disease. To study roles for MYCN amplification in SCLC progression and chemoresistance, we developed a genetically engineered mouse model of MYCN-overexpressing SCLC. In treatment-naïve mice, MYCN overexpression promoted cell cycle progression, suppressed infiltration of cytotoxic T cells, and accelerated SCLC. MYCN overexpression also suppressed response to cisplatin-etoposide chemotherapy, with similar findings made upon MYCL overexpression. We extended these data to genetically perturb chemosensitive patient-derived xenograft (PDX) models of SCLC. In chemosensitive PDX models, overexpression of either MYCN or MYCL also conferred a switch to chemoresistance. To identify therapeutic strategies for MYCN-overexpressing SCLC, we performed a genome-scale CRISPR-Cas9 sgRNA screen. We identified the deubiquitinase USP7 as a MYCN-associated synthetic vulnerability. Pharmacological inhibition of USP7 resensitized chemoresistant MYCN-overexpressing PDX models to chemotherapy in vivo. Our findings show that MYCN overexpression drives SCLC chemoresistance and provide a therapeutic strategy to restore chemosensitivity.

| S-EPMC7462062 | biostudies-literature

MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity [tumor]

Project description:This study assessed gene expression in mouse SCLC with inducible MYCN overexpression in tumors

2020-12-05 | GSE162680 | GEO

MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity [cells]

Project description:This study assessed gene expression in mouse SCLC with inducible MYCN overexpression

2020-12-05 | GSE162679 | GEO

MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity

Project description:MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity

| PRJNA682599 | ENA

MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity [cells]

Project description:MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity [cells]

| PRJNA682605 | ENA

MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity [tumor]

Project description:MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity [tumor]

| PRJNA682606 | ENA

DNA-PK inhibition by M3814 enhances chemosensitivity in non-small cell lung cancer.

Project description:A significant proportion of non-small cell lung cancer (NSCLC) patients experience accumulating chemotherapy-related adverse events, motivating the design of chemosensitizating strategies. The main cytotoxic damage induced by chemotherapeutic agents is DNA double-strand breaks (DSB). It is thus conceivable that DNA-dependent protein kinase (DNA-PK) inhibitors which attenuate DNA repair would enhance the anti-tumor effect of chemotherapy. The present study aims to systematically evaluate the efficacy and safety of a novel DNA-PK inhibitor M3814 in synergy with chemotherapies on NSCLC. We identified increased expression of DNA-PK in human NSCLC tissues which was associated with poor prognosis. M3814 potentiated the anti-tumor effect of paclitaxel and etoposide in A549, H460 and H1703 NSCLC cell lines. In the four combinations based on two NSCLC xenograft models and two chemotherapy, we also observed tumor regression at tolerated doses in vivo. Moreover, we identified a P53-dependent accelerated senescence response by M3814 following treatment with paclitaxel/etoposide. The present study provides a theoretical basis for the use of M3814 in combination with paclitaxel and etoposide in clinical practice, with hope to aid the optimization of NSCLC treatment.

| S-EPMC8727896 | biostudies-literature

MYCN-mediated regulation of the HES1 promoter enhances the chemoresistance of small-cell lung cancer by modulating apoptosis.

Project description:MYCN, a member of the MYC family, is correlated with tumorigenesis, metastasis and therapy in many malignancies; however, its role in small-cell lung cancer (SCLC) remains unclear. In this study, we sought to identify the function of MYCN in SCLC chemoresistance and found that MYCN is overexpressed in chemoresistant SCLC cells. We used MYCN gain- and loss-of- function experiments to demonstrate that MYCN promotes in vitro and in vivo chemoresistance in SCLC by inhibiting apoptosis. Mechanistic investigations showed that MYCN binds to the HES1 promoter and exhibits transcriptional activity. Furthermore, MYCN mediated SCLC chemoresistance through HES1. Accordingly, the NOTCH inhibitor FLI-60 derepressed HES1 and diminished MYCN-induced chemoresistance in SCLC. Finally, the positive correlation between HES1 and MYCN was confirmed in SCLC patients. Chemoresistant SCLC patients had higher expression levels of MYCN and HES1 than patients without chemoresistant SCLC. MYCN overexpression was related to advanced clinical stage and shorter survival in SCLC. In conclusion, our study revealed that MYCN and HES1 may be potential therapeutic targets and promising predictors for SCLC.

| S-EPMC6780666 | biostudies-literature

Tudor staphylococcal nuclease drives chemoresistance of non-small cell lung carcinoma cells by regulating S100A11.

Project description:Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC), the major lung cancer subtype, is characterized by high resistance to chemotherapy. Here we demonstrate that Tudor staphylococcal nuclease (SND1 or TSN) is overexpressed in NSCLC cell lines and tissues, and is important for maintaining NSCLC chemoresistance. Downregulation of TSN by RNAi in NSCLC cells led to strong potentiation of cell death in response to cisplatin. Silencing of TSN was accompanied by a significant decrease in S100A11 expression at both mRNA and protein level. Downregulation of S100A11 by RNAi resulted in enhanced sensitivity of NSCLC cells to cisplatin, oxaliplatin and 5-fluouracil. AACOCF(3), a phospholipase A(2) (PLA(2)) inhibitor, strongly abrogated chemosensitization upon silencing of S100A11 suggesting that PLA(2) inhibition by S100A11 governs the chemoresistance of NSCLC. Moreover, silencing of S100A11 stimulated mitochondrial superoxide production, which was decreased by AACOCF(3), as well as N-acetyl-L-cysteine, which also mimicked the effect of PLA(2) inhibitor on NSCLC chemosensitization upon S100A11 silencing. Thus, we present the novel TSN-S100A11-PLA(2) axis regulating superoxide-dependent apoptosis, triggered by platinum-based chemotherapeutic agents in NSCLC that may be targeted by innovative cancer therapies.

| S-EPMC4494929 | biostudies-literature

Nobiletin Enhances Chemosensitivity to Adriamycin through Modulation of the Akt/GSK3β/β⁻Catenin/MYCN/MRP1 Signaling Pathway in A549 Human Non-Small-Cell Lung Cancer Cells.

Project description:Drug resistance is a major problem in the treatment of non-small-cell lung cancer (NSCLC). In this study, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed to identify the differentially expressed genes in Adriamycin (ADR)-resistant NSCLC A549/ADR cells compared with parental A549 cells. Among the tested phytochemicals, nobiletin (NBT) is able to overcome the ADR resistance of A549/ADR cells. NBT treatment decreased the expression of a neuroblastoma-derived MYC (MYCN) and multidrug resistance-associated protein 1 (MRP1) as well as downregulating Akt, GSK3β, and β-catenin. Consistent with these results, NBT treatment resulted in the accumulation of intracellular ADR. A combination index (CI) assay confirmed the synergistic effect of combined treatment with NBT and ADR in reducing the viability of A549/ADR cells (CI = 0.152). Combined treatment with NBT and ADR enhanced apoptosis in A549/ADR cells, as evidenced by increased caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage, and sub-G1 population compared to treatment with ADR alone. In vivo experiments using a mouse xenograft model revealed that combination therapy with NBT and ADR significantly reduced tumor volume by 84.15%. These data suggest that NBT can sensitize ADR-induced cytotoxicity against A549/ADR cells by inhibiting MRP1 expression, indicating that NBT could serve as an effective adjuvant agent for ADR-based chemotherapy in lung cancer.

| S-EPMC6316077 | biostudies-literature

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