Journal
CLINICAL CANCER RESEARCH
Volume 25, Issue 19, Pages 5984-5996Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-3399
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Funding
- NIH [R35 CA197731-01]
- Chemical Biology Core Facility at the H. Lee Moffitt Cancer Center & Research Institute
- an NCI-designated Comprehensive Cancer Center [P30-CA076292]
- MD Anderson Cancer Center [P30-CA016672]
- Molecular Genomics Core Facility at the H. Lee Moffitt Cancer Center & Research Institute
- an NCI-designated Comprehensive Cancer Center [P30-CA076292]
- SAIL Core Facility at the H. Lee Moffitt Cancer Center & Research Institute
- an NCI-designated Comprehensive Cancer Center [P30-CA076292]
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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 FGTI2734 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 fromfour 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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