Development of pancreatic cancer therapeutics by the oxidative drug combination targeting KRAS mutant cancer cells

      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:

Full name

Identifier

Links

Dos Sarbasov, PhD

Scopus Author ID:  6506192345

 

ORCID: 0000-0002-6848-1

 

Web of Science Researcher ID: AAS-4950-2020

 

Researcher ID in Publons AAS-4950-2020

https://www.scopus.com/authid/detail.uri?authorId= 6506192345

 

https://orcid.org/0000-0002-6848-1

 

 

https://www.webofscience.com/wos/author/record/0000-0002-6848-1

 

 

Dinara Begimbetova, PhD

Scopus Author ID: 17433295400 

 

ORCID: 0000-0002-0643-6257

 

Web of Science Researcher ID N-4585-2017

https://orcid.org/ 0000-0002-0643-6257

 

 

 

https://orcid.org/ 0000-0002-0643-6257

 

 

https://orcid.org/ 0000-0002-0643-6257

Vladimir Kiyan, PhD

Scopus Author ID – 6701646393

 

Researcher ID - O-7403-2017

 

ORCID – 0000-0001-9787-9151

https://www.scopus.com/authid/detail.uri?authorId=6701646393

 

https://publons.com/researcher/1596462/vladimir-kiyan/

 

 

https://orcid.org/0000-0001-9787-9151

Ainur Akilzhanova, MD, PhD, Professor

 

 

Scopus Author ID – 13612246000

 

ORCID 0000-0001-6161-8355

 

Web of Science ResearcherID 
N-6931-2015

 

https://www.scopus.com/authid/detail.uri?authorId=13612246000

 

https://orcid.org/0000-0001-6161-8355

 

 

 

https://www.webofscience.com/wos/author/record/0000-0002-6848-1

 

Ulykbek Kairov Yerulanovich, PhD

Scopus Author ID – 55549951000

 

Web of Science ResearcherID 
J-1625-2014

https://www.scopus.com/authid/detail.uri?authorId=55549951000

 

 

https://www.webofscience.com/wos/author/record/J-1625-2014

 

Publications in 2021: No