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

Sci Rep. 2020 Nov 26;10(1):20662. doi: 10.1038/s41598-020-77373-8.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinar Cells / drug effects
  • Acinar Cells / metabolism
  • Acinar Cells / pathology
  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Calcium / metabolism
  • Carcinogenesis / drug effects
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Dedifferentiation / drug effects
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / metabolism
  • Cells, Cultured
  • Ceruletide / metabolism
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Disease Progression
  • GTP-Binding Proteins / metabolism
  • Gemcitabine
  • Histone Deacetylase Inhibitors / pharmacology
  • Mice
  • Pancreatic Ducts / drug effects
  • Pancreatic Ducts / metabolism
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Pancreatitis / drug therapy
  • Pancreatitis / metabolism
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • RGS Proteins / metabolism
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • RGS Proteins
  • RGS16 protein
  • Deoxycytidine
  • Ceruletide
  • GTP-Binding Proteins
  • Proto-Oncogene Proteins p21(ras)
  • Calcium
  • Gemcitabine