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MYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostat
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MYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostat
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Journal Article
MYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostat
2023
Overview
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.
Publisher
BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
Subject
/ Animals
/ Biomedical and Life Sciences
/ Cancer
/ Ethics
/ Genetically modified organisms
/ Histone Deacetylase Inhibitors - pharmacology
/ Histone Deacetylase Inhibitors - therapeutic use
/ Humans
/ Lung Neoplasms - drug therapy
/ Lungs
/ Mice
/ MYC
/ Oncology
/ Phosphatidylinositol 3-Kinases
/ Proto-Oncogene Proteins c-myc - metabolism
/ Robotics
/ Small Cell Lung Carcinoma - drug therapy
/ Small Cell Lung Carcinoma - genetics
/ Tumors
