Project: Development of pancreatic cancer therapeutics by the oxidative drug combination targeting KRAS mutant cancer cells
IRN АР08857553
Introduction: The Kirsten rat sarcoma (KRAS) gene mutations lead to highly malignant human cancers with a poor clinical outcome. Activating KRAS mutations occur predominately in pancreatic cancer and are found in almost all (95%) of pancreatic ductal adenocarcinomas (PDACs). They are also common in biliary tract (33%), colorectal (32%), lung (19%) and ovarian (17%) cancers. There are no effective therapies have been developed to treat the KRAS mutant cancers, because it encodes a small GTPase that does not provide any distinctive “druggable” pocket for targeting.
Goal: The main goal is to develop the oxidizing drug combination to treat pancreatic cancer patients. We propose to define a cytotoxic mechanism of ATO / D-VC combination (Aim I) and to determine an efficacy of the drug combination in suppression of pancreatic cancer mouse models (Aim 2).
Expected results:
Biochemical studies of mitochondrial-dependent ROS production will be carried out. induced combination of ATO/D-VC in KRAS mutant pancreatic cancer cells: regulation of ROS detection method. Work will begin to determine the effectiveness of the ATО / D-VС drug combination in suppressing PDAC oncology in a mouse transgenic model. Targeted inhibition of mitochondrial ETC in KRAS mutant pancreatic cancer cells with ATO / D-VC combination and the study of ROS generation in mitochondria will be carried out. Biochemical studies will be carried out to determine the thiol-reactive proteins of ETCS that mediate the mitochondrial-dependent generation of cytotoxic ROS using a combination of ATO / D-VC drugs.
Current results:
Biochemical studies of mitochondrial-dependent ROS production induced by the ALT/D-VC combination in KRAS mutant pancreatic cancer cells were carried out and the ROS detection method was regulated. The obtained results demonstrate the synergistic effect of ATA and DVD selectively inducing a strong cytotoxic effect in KRAS mutant cancer cells. A significant enrichment of Core protein 1 and Rieske Fe-S protein was observed in the collected thiol-reactive mitochondrial fraction obtained from cells treated with ATO/D-VC. The most aggressive growth was observed in a sample of PDAC-6 cancer cells. We have created a PDAC cancer cell line: PDAC-6. Genomic profiling of the KRAS gene revealed its mutation in exon 2: KRASG12D. TO/DVK is effective in suppressing tumor growth of mutant PDAC KRASG12D tumors.
Research group:
Publications in 2021: No