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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2023 | Lung Cancer | Research

MYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostat

Authors: Jasmine Chen, Aleks C. Guanizo, W. Samantha N. Jakasekara, Chaitanya Inampudi, Quinton Luong, Daniel J. Garama, Muhammad Alamgeer, Nishant Thakur, Michael DeVeer, Vinod Ganju, D. Neil Watkins, Jason E. Cain, Daniel J. Gough

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2023

Abstract

Background

Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with an appalling overall survival of less than 5% (Zimmerman et al. J Thor Oncol 14:768-83, 2019). Patients typically respond to front line platinum-based doublet chemotherapy, but almost universally relapse with drug resistant disease. Elevated MYC expression is common in SCLC and has been associated with platinum resistance. This study evaluates the capacity of MYC to drive platinum resistance and through screening identifies a drug capable of reducing MYC expression and overcoming resistance.

Methods

Elevated MYC expression following the acquisition of platinum resistance in vitro and in vivo was assessed. Moreover, the capacity of enforced MYC expression to drive platinum resistance was defined in SCLC cell lines and in a genetically engineered mouse model that expresses MYC specifically in lung tumors. High throughput drug screening was used to identify drugs able to kill MYC-expressing, platinum resistant cell lines. The capacity of this drug to treat SCLC was defined in vivo in both transplant models using cell lines and patient derived xenografts and in combination with platinum and etoposide chemotherapy in an autochthonous mouse model of platinum resistant SCLC.

Results

MYC expression is elevated following the acquisition of platinum resistance and constitutively high MYC expression drives platinum resistance in vitro and in vivo. We show that fimepinostat decreases MYC expression and that it is an effective single agent treatment for SCLC in vitro and in vivo. Indeed, fimepinostat is as effective as platinum-etoposide treatment in vivo. Importantly, when combined with platinum and etoposide, fimepinostat achieves a significant increase in survival.

Conclusions

MYC is a potent driver of platinum resistance in SCLC that is effectively treated with fimepinostat.

Available only for authorised users

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Title: MYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostat
Authors: Jasmine Chen
Aleks C. Guanizo
W. Samantha N. Jakasekara
Chaitanya Inampudi
Quinton Luong
Daniel J. Garama
Muhammad Alamgeer
Nishant Thakur
Michael DeVeer
Vinod Ganju
D. Neil Watkins
Jason E. Cain
Daniel J. Gough
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Lung Cancer
Lung Cancer
SCLC
Lung Cancer
SCLC
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2023
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-023-02678-1

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Abstract

Background

Methods

Results

Conclusions

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