Dual farnesyl and geranylgeranyl transferase inhibitor thwarts mutant KRAS-driven patient-derived pancreatic tumors

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)5984-5996
Number of pages13
JournalClinical Cancer Research
Volume25
Issue number19
DOIs
StatePublished - Oct 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kazi, A., Xiang, S., Yang, H., Chen, L., Kennedy, P., Ayaz, M., Fletcher, S., Cummings, C., Lawrence, H. R., Beato, F., Kang, Y., Kim, M. P., Delitto, A., Underwood, P. W., Fleming, J. B., Trevino, J. G., Hamilton, A. D., & Sebti, S. M. (2019). Dual farnesyl and geranylgeranyl transferase inhibitor thwarts mutant KRAS-driven patient-derived pancreatic tumors. Clinical Cancer Research, 25(19), 5984-5996. https://doi.org/10.1158/1078-0432.CCR-18-3399