TY - JOUR
T1 - Dual farnesyl and geranylgeranyl transferase inhibitor thwarts mutant KRAS-driven patient-derived pancreatic tumors
AU - Kazi, Aslamuzzaman
AU - Xiang, Shengyan
AU - Yang, Hua
AU - Chen, Liwei
AU - Kennedy, Perry
AU - Ayaz, Muhammad
AU - Fletcher, Steven
AU - Cummings, Christopher
AU - Lawrence, Harshani R.
AU - Beato, Francisca
AU - Kang, Ya'an
AU - Kim, Michael P.
AU - Delitto, Andrea
AU - Underwood, Patrick W.
AU - Fleming, Jason B.
AU - Trevino, Jose G.
AU - Hamilton, Andrew D.
AU - Sebti, Said M.
N1 - Funding Information:
This work was funded in part by NIH grant R35 CA197731-01 (to S.M. Sebti, PhD) and was supported in part by the Chemical Biology, Molecular Genomics and SAIL Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute; an NCI-designated Comprehensive Cancer Center (P30-CA076292). We thank these cores for their outstanding assistance and expertise. Part of the work was also supported in part by MD Anderson Cancer Center P30-CA016672. We also thank Michelle Blaskovich for technical assistance and Rasa Hamilton for editorial assistance. Synthesis of some of the compounds reported in this article was supported by NIH grant R50CA211447 (to H.R. Lawrence).
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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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U2 - 10.1158/1078-0432.CCR-18-3399
DO - 10.1158/1078-0432.CCR-18-3399
M3 - Article
C2 - 31227505
AN - SCOPUS:85072819941
SN - 1078-0432
VL - 25
SP - 5984
EP - 5996
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -