(not so much because I'm interested, more just from following up on today's kura news).....
Clin Cancer Res. 2019 Oct 1;25(19):5984-5996. doi: 10.1158/1078-0432.CCR-18-3399. Epub 2019 Jun 21.
Dual Farnesyl and Geranylgeranyl Transferase Inhibitor Thwarts Mutant KRAS-Driven Patient-Derived Pancreatic Tumors.
Kazi A1,2, Xiang S1, Yang H1, Chen L1, Kennedy P1, Ayaz M1,3, Fletcher S4, Cummings C5, Lawrence HR1,2,3, Beato F6, Kang Y7, Kim MP7, Delitto A8, Underwood PW8, Fleming JB6, Trevino JG8, Hamilton AD5, Sebti SM9,2,3.
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.
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. |
