The KRAS gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes: HRAS and NRAS. These proteins play important roles in cell division, cell differentiation, and the self-destruction of cells apoptosis. Mutant KRAS drives pancreatic oncogenesis, yet there are no drugs in the clinic to target mutant KRAS. In this study, Aslamuzzaman Kazi,et al report on the development of a novel peptidomimetic dual farnesyl/geranylgeranyl transferase inhibitor FGTI-2734.
FGTI-2734 thwarts mutant KRAS patient-derived pancreatic tumors. Importantly, FGTI-2734 inhibits membrane localization of KRAS in pancreatic, lung, and colon human cancer cells. FGTI-2734 induces apoptosis and inhibits the growth in mice of mutant KRAS-dependent but not mutant KRAS-independent human tumors. Finally, FGTI-2734 is also highly effective at inhibiting, in three-dimensional co-cultures with resistance-promoting pancreatic stellate cells, the viability of primary and metastatic mutant KRAS tumor cells derived from pancreatic cancer patients.
FGTI-2734 prevents KRAS membrane localization. Particularly, FGTI-2734 inhibits the growth of mutant KRAS-dependent but not mutant KRAS-independent human tumors in mouse xenograft models. Besides, FGTI-2734 inhibits the growth of mutant KRAS patient-derived xenografts from pancreatic cancer patients. Especially, FGTI-2734 suppresses oncogenic signaling pathways mediated by AKT, mTOR, and cMYC while upregulating the tumor suppressor p53. Researchers find that FGTI-2734 effectively inhibits KRAS membrane localization and growth of mutant KRAS-dependent tumors at non-toxic doses.
All in all, FGTI-2734 is a single agent is lethal to low-passage primary and metastatic mutant KRAS adenocarcinoma cells derived from pancreatic cancer patients.