MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity
Autor: | Xiaoli Liu, Justin P. Norton, Deshui Jia, Renato G. Martins, Emily Eastwood, Huajia Zhang, Paul Leger, Keith D. Eaton, Eli Grunblatt, Nan Wu, Yamini M. Ohol, Rhiana Thomas, David MacPherson, A. McGarry Houghton, Joseph B. Hiatt, Ali H. Ibrahim, Ryan Basom |
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Rok vydání: | 2020 |
Předmět: |
0303 health sciences
Chemotherapy biology medicine.medical_treatment Neuroendocrine Cancer respiratory tract diseases Deubiquitinating enzyme 03 medical and health sciences 0302 clinical medicine In vivo 030220 oncology & carcinogenesis Genetically Engineered Mouse Genetics medicine Cancer research biology.protein Cytotoxic T cell Non small cell neoplasms Research Paper 030304 developmental biology Developmental Biology Therapeutic strategy |
Zdroj: | Genes Dev |
ISSN: | 1549-5477 0890-9369 |
Popis: | 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. |
Databáze: | OpenAIRE |
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