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

Grunblatt, Eli; Wu, Nan; Zhang, Huajia; Liu, Xiaoli; Norton, Justin P.; Ohol, Yamini M.; Leger, Paul R.; Hiatt, Joseph; Eastwood, Emily; Thomas, Rhiana; Ibrahim, Ali H.; Jia, Deshui; Basom, Ryan; Eaton, Keith D.; Martins, Renato; Houghton, A. McGarry; MacPherson, David

doi:10.1101/gad.340133.120

Cited by 65 publications

(36 citation statements)

References 73 publications

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“…In a matched pair of CDX, the percentage of MYC + cells increased with tumor progression, concordant with increased expression of Notch signaling and EMT markers ( Simpson et al 2020 ). These findings are consistent in GEMMs, where high expression of MYC or MYCN and low expression of NE markers correspond with poor response to chemotherapy ( Mollaoglu et al 2017 ; Grunblatt et al 2020 ). In human cell lines, MYC protein levels also increased (while MYCL decreased) following selection for chemoresistance ( Wagner et al 2018 ; Chalishazar et al 2019 ; Huang et al 2021 ).…”

Section: A Revised and Evolving Classification Scheme Based On Lineag...supporting

confidence: 78%

Killing SCLC: insights into how to target a shapeshifting tumor

2022

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Small cell lung cancer (SCLC) is a rapidly growing, highly metastatic, and relatively immune-cold lung cancer subtype. Historically viewed in the laboratory and clinic as a single disease, new discoveries suggest that SCLC comprises multiple molecular subsets. Expression of MYC family members and lineage-related transcription factors ASCL1, NEUROD1, and POU2F3 (and, in some studies, YAP1) define unique molecular states that have been associated with distinct responses to a variety of therapies. However, SCLC tumors exhibit a high degree of intratumoral heterogeneity, with recent studies suggesting the existence of tumor cell plasticity and phenotypic switching between subtype states. While SCLC plasticity is correlated with, and likely drives, therapeutic resistance, the mechanisms underlying this plasticity are still largely unknown. Subtype states are also associated with immune-related gene expression, which likely impacts response to immune checkpoint blockade and may reveal novel targets for alternative immunotherapeutic approaches. In this review, we synthesize recent discoveries on the mechanisms of SCLC plasticity and how these processes may impinge on antitumor immunity.

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Section: A Revised and Evolving Classification Scheme Based On Lineag...supporting

confidence: 78%

Killing SCLC: insights into how to target a shapeshifting tumor

2022

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“…33,35 The abnormal expression of MYCN was found in neurogenic tumors, including neuroblastoma, neuroendocrine prostate cancer and small cell lung cancer. [36][37][38][39][40]…”

Section: Discussionmentioning

confidence: 99%

CircPTCH1 Promotes Migration in Lung Cancer by Regulating MYCN Expression Through miR-34c-5p

Shen¹,

Sun²

2021

OTT

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Background The incidence rate and mortality rate of lung cancer are the highest in the world. Therefore, further studies are needed to reveal the molecular mechanism of lung cancer progression and development. Previous study demonstrated that the deregulation of circRNAs can regulate cell biological functions in tumorigenesis and development. However, the roles of circPTCH1 in lung cancer have not yet been revealed. Materials and Methods The expression levels of circPTCH1, miR-34c-5p, and MYCN were measured by RT-PCR in lung cancer tissues and cells; dual-luciferase reporter and RIP assay showed that circRNA served as a sponge for miRNA, and miRNA could target mRNA. In vitro, effects of si-circPTCH1 can regulate lung cancer cells’ migration, invasion were detected by CCK-8 assay, wound healing assay, and transwell assay. Results Our research demonstrated that the expression of circPTCH1 was upregulated in lung cancer tissues and cell lines and increased in metastatic tissues compared to that of non-metastatic tissues. circPTCH1 sponging miR-34c-5p to target MYCN was revealed by dual-luciferase reporter and a RIP assay. In addition, the expression level of miR-34c-5p was reduced in lung cancer tumor tissues, and MYCN was significantly increased in lung cancer tumor tissues. Pearson correlation analysis showed that miR-34c-5p with circPTCH1 and MYCN had a moderately negative correlation, and there was a moderately positive correlation between circPTCH1 and MYCN. Further, cytological studies found that circPTCH1 reduced lung cancer cells’ migration and invasion by targeting MYCN via miR-34c-5p. Conclusion circPTCH1 plays a tumor enhancement role in lung cancer and that can effectively promote migration, invasion and EMT by targeting the miR-34c-5p/MYCN axis. circPTCH1 may be a novel potential treatment and diagnosis biomarker for lung cancer.

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“…Using a PDX model, Grunblatt et al identified the deubiquitinase USP7 as a MYCN-associated synthetic vulnerability in small cell lung cancer (SCLC) by a genome-scale CRISPR-Cas9 screening. Pharmacological inhibition of USP7 re-sensitized chemo-resistant MYCN-overexpressing PDX models to chemotherapy in vivo ( 218 ). Similarly, dihydroorotate dehydrogenase was also identified as a therapeutic target in SCLC cells ( 219 ).…”

Section: The Combined Application Of the Crispr-cas9 Screening And Pa...mentioning

confidence: 99%

Evolution of Molecular Targeted Cancer Therapy: Mechanisms of Drug Resistance and Novel Opportunities Identified by CRISPR-Cas9 Screening

Hou

Liu

et al. 2022

Front. Oncol.

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Molecular targeted therapy has revolutionized the landscape of cancer treatment due to better therapeutic responses and less systemic toxicity. However, therapeutic resistance is a major challenge in clinical settings that hinders continuous clinical benefits for cancer patients. In this regard, unraveling the mechanisms of drug resistance may identify new druggable genetic alterations for molecularly targeted therapies, thus contributing to improved therapeutic efficacies. The recent rapid development of novel methodologies including CRISPR-Cas9 screening technology and patient-derived models provides powerful tools to dissect the underlying mechanisms of resistance to targeted cancer therapies. In this review, we updated therapeutic targets undergoing preclinical and clinical evaluation for various cancer types. More importantly, we provided comprehensive elaboration of high throughput CRISPR-Cas9 screening in deciphering potential mechanisms of unresponsiveness to molecularly targeted therapies, which will shed light on the discovery of novel opportunities for designing next-generation anti-cancer drugs.

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

Cited by 65 publications

References 73 publications

Killing SCLC: insights into how to target a shapeshifting tumor

Killing SCLC: insights into how to target a shapeshifting tumor

CircPTCH1 Promotes Migration in Lung Cancer by Regulating MYCN Expression Through miR-34c-5p

Evolution of Molecular Targeted Cancer Therapy: Mechanisms of Drug Resistance and Novel Opportunities Identified by CRISPR-Cas9 Screening

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