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

Abstract：

: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.

journal_name

Genes Dev

journal_title

Genes & development

authors

Grunblatt E,Wu N,Zhang H,Liu X,Norton JP,Ohol Y,Leger P,Hiatt JB,Eastwood EC,Thomas R,Ibrahim AH,Jia D,Basom R,Eaton KD,Martins R,Houghton AM,MacPherson D

doi

10.1101/gad.340133.120

subject

Has Abstract

pub_date

2020-09-01 00:00:00

pages

1210-1226

issue

17-18

eissn

0890-9369

issn

1549-5477

pii

gad.340133.120

journal_volume

34

pub_type

杂志文章

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