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

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dc.contributor.authorChen, Jasmine
dc.contributor.authorGuanizo, Aleks C.
dc.contributor.authorJakasekara, W. S. N.
dc.contributor.authorInampudi, Chaitanya
dc.contributor.authorLuong, Quinton
dc.contributor.authorGarama, Daniel J.
dc.contributor.authorAlamgeer, Muhammad
dc.contributor.authorThakur, Nishant
dc.contributor.authorDeVeer, Michael
dc.contributor.authorGanju, Vinod
dc.contributor.authorWatkins, D. N.
dc.contributor.authorCain, Jason E.
dc.contributor.authorGough, Daniel J.
dc.date.accessioned2023-05-01T15:15:52Z
dc.date.available2023-05-01T15:15:52Z
dc.date.issued2023-04-26
dc.date.updated2023-05-01T03:11:07Z
dc.description.abstractAbstract 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.en_US
dc.identifier.citationJournal of Experimental & Clinical Cancer Research. 2023 Apr 26;42(1):100
dc.identifier.citationJournal of Experimental & Clinical Cancer Research. 2023 Apr 26;42(1):100
dc.identifier.urihttps://doi.org/10.1186/s13046-023-02678-1
dc.identifier.urihttp://hdl.handle.net/1993/37310
dc.language.isoengen_US
dc.language.rfc3066en
dc.publisherBioMed Central (BMC)en_US
dc.rightsopen accessen_US
dc.rights.holderThe Author(s)
dc.titleMYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostaten_US
dc.typejournal articleen_US
local.author.affiliationRady Faculty of Health Sciences::Max Rady College of Medicine::Department of Internal Medicineen_US
oaire.citation.issue1en_US
oaire.citation.startPage100en_US
oaire.citation.titleJournal of Experimental & Clinical Cancer Researchen_US
oaire.citation.volume42en_US
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