Dual Farnesyl and Geranylgeranyl Transferase Inhibitor Thwarts Mutant KRAS-Driven Patient-Derived Pancreatic Tumors

Clin Cancer Res. 2019 Oct 1;25(19):5984-5996. doi: 10.1158/1078-0432.CCR-18-3399. Epub 2019 Jun 21.


Purpose: Mutant KRAS is a major driver of pancreatic oncogenesis and therapy resistance, yet KRAS inhibitors are lacking in the clinic. KRAS requires farnesylation for membrane localization and cancer-causing activity prompting the development of farnesyltransferase inhibitors (FTIs) as anticancer agents. However, KRAS becomes geranylgeranylated and active when cancer cells are treated with FTIs. To overcome this geranylgeranylation-dependent resistance to FTIs, we designed FGTI-2734, a RAS C-terminal mimetic dual FT and geranylgeranyltransferase-1 inhibitor (GGTI).

Experimental design: Immunofluorescence, cellular fractionation, and gel shift assays were used to assess RAS membrane association, Western blotting to evaluate FGTI-2734 effects on signaling, and mouse models to demonstrate its antitumor activity.

Results: FGTI-2734, but not the selective FTI-2148 and GGTI-2418, inhibited membrane localization of KRAS in pancreatic, lung, and colon human cancer cells. FGTI-2734 induced apoptosis and inhibited the growth in mice of mutant KRAS-dependent but not mutant KRAS-independent human tumors. Importantly, FGTI-2734 inhibited the growth of xenografts derived from four patients with pancreatic cancer with mutant KRAS (2 G12D and 2 G12V) tumors. FGTI-2734 was also highly effective at inhibiting, in three-dimensional cocultures with resistance promoting pancreatic stellate cells, the viability of primary and metastatic mutant KRAS tumor cells derived from eight patients with pancreatic cancer. Finally, FGTI-2734 suppressed oncogenic pathways mediated by AKT, mTOR, and cMYC while upregulating p53 and inducing apoptosis in patient-derived xenografts in vivo.

Conclusions: The development of this novel dual FGTI overcomes a major hurdle in KRAS resistance, thwarting growth of patient-derived mutant KRAS-driven xenografts from patients with pancreatic cancer, and as such it warrants further preclinical and clinical studies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Alkyl and Aryl Transferases / metabolism
  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Enzyme Inhibitors / pharmacology*
  • Farnesyltranstransferase / antagonists & inhibitors*
  • Farnesyltranstransferase / metabolism
  • Humans
  • Male
  • Mice
  • Mice, SCID
  • Mutation*
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Signal Transduction
  • Xenograft Model Antitumor Assays


  • Enzyme Inhibitors
  • KRAS protein, human
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • Farnesyltranstransferase
  • Proto-Oncogene Proteins p21(ras)