Concerted cell and in vivo screen for pancreatic ductal adenocarcinoma (PDA) chemotherapeutics

Somayeh Layeghi-Ghalehsoukhteh, Shreoshi Pal Choudhuri, Ozhan Ocal, Yalda Zolghadri, Victor Pashkov, Hanspeter Niederstrasser, Bruce A. Posner, Havish S. Kantheti, Ana C. Azevedo-Pouly, Huocong Huang, Luc Girard, Raymond J. MacDonald, Rolf A. Brekken, Thomas M. Wilkie

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


PDA is a major cause of US cancer-related deaths. Oncogenic Kras presents in 90% of human PDAs. Kras mutations occur early in pre-neoplastic lesions but are insufficient to cause PDA. Other contributing factors early in disease progression include chronic pancreatitis, alterations in epigenetic regulators, and tumor suppressor gene mutation. GPCRs activate heterotrimeric G-proteins that stimulate intracellular calcium and oncogenic Kras signaling, thereby promoting pancreatitis and progression to PDA. By contrast, Rgs proteins inhibit Gi/q-coupled GPCRs to negatively regulate PDA progression. Rgs16::GFP is expressed in response to caerulein-induced acinar cell dedifferentiation, early neoplasia, and throughout PDA progression. In genetically engineered mouse models of PDA, Rgs16::GFP is useful for pre-clinical rapid in vivo validation of novel chemotherapeutics targeting early lesions in patients following successful resection or at high risk for progressing to PDA. Cultured primary PDA cells express Rgs16::GFP in response to cytotoxic drugs. A histone deacetylase inhibitor, TSA, stimulated Rgs16::GFP expression in PDA primary cells, potentiated gemcitabine and JQ1 cytotoxicity in cell culture, and Gem + TSA + JQ1 inhibited tumor initiation and progression in vivo. Here we establish the use of Rgs16::GFP expression for testing drug combinations in cell culture and validation of best candidates in our rapid in vivo screen.

Original languageEnglish (US)
Article number20662
JournalScientific reports
Issue number1
StatePublished - Dec 2020

ASJC Scopus subject areas

  • General


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