2. Academic Validation
  3. Dual Farnesyl and Geranylgeranyl Transferase Inhibitor Thwarts Mutant KRAS-Driven Patient-Derived Pancreatic Tumors

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.
Aslamuzzaman Kazi 1 2,  Shengyan Xiang 1,  Hua Yang 1,  Liwei Chen 1,  Perry Kennedy 1,  Muhammad Ayaz 1 3,  Steven Fletcher 4,  Christopher Cummings 5,  Harshani R Lawrence 1 2 3,  Francisca Beato 6,  Ya'an Kang 7,  Michael P Kim 7,  Andrea Delitto 8,  Patrick W Underwood 8,  Jason B Fleming 6,  Jose G Trevino 8,  Andrew D Hamilton 5,  Said M Sebti 9 2 3
Affiliations

Affiliations

  • 1 Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
  • 2 Department of Oncologic Sciences, University of South Florida, Tampa, Florida.
  • 3 Chemical Biology Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
  • 4 University of Toronto, Ontario, Canada.
  • 5 Department of Chemistry, Yale University, New Haven, Connecticut.
  • 6 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
  • 7 Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 8 Department of Surgery, University of Florida, Gainesville, Florida.
  • 9 Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. said.sebti@vcuhealth.org.
PMID: 31227505 DOI: 10.1158/1078-0432.CCR-18-3399
Abstract

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.

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