Open Access Peer-reviewed Research Article

Efficacy and mechanism of KRAS G12C PROTAC in inhibiting the proliferation of pancreatic cancer cells

Article Sidebar

PKD-1 promoted the degradation
Download PDF
Submitted   Dec 24, 2021
Published   Jan 11, 2022
Issue    Vol 3 No 1 (2021)
DOI   10.25082/JPBR.2021.01.002

Views

2717

Downloads

817

Citations

PlumX Metrics

Main Article Content

Shuai Gao
College of Pharmacy, Yantai University, Yantai 264000, Shandong Province, China
Fangxia Zou
College of Pharmacy, Yantai University, Yantai 264000, Shandong Province, China
Lixia Zheng
Shandong Luye Pharmaceutical Co. Ltd., Yantai 264000, Shandong Province, China
Yunjie Wang
College of Pharmacy, Yantai University, Yantai 264000, Shandong Province, China
Xinyu Feng
College of Pharmacy, Yantai University, Yantai 264000, Shandong Province, China
Deshuai Liu
College of Pharmacy, Yantai University, Yantai 264000, Shandong Province, China
Yutong Mao
College of Pharmacy, Yantai University, Yantai 264000, Shandong Province, China
Liang Ye corresponding author
School of Public Health and Management, Binzhou Medical University, Yantai 264000, Shandong Province, China
Jingwei Tian
College of Pharmacy, Yantai University, Yantai 264000, Shandong Province, China

Abstract

Pancreatic cancer is a rare but highly malignant cancer with few effective treatments available. Targeting cancers bearing specific genetic mutations offers a new approach for cancer therapy. PROTAC (proteolysis-targeting chimeras) is an emerging technique to design targeted therapy and increasing evidence supports its utility. This study examined the in vitro pharmacodynamics and mechanism of PROTAC K-Ras Degrader-1 (PKD-1), a PROTAC molecule, in inhibiting the proliferation of pancreatic cancer cells. We used a pancreatic cancer cell line, MIA PaCa-2 cells, to examined the binding and degradation-promoting capabilities of PKD-1 on KRAS G12C protein and further evaluated the effects of PKD-1 on cell viability, cell cycle and apoptosis. PKD-1 was able to bind to KRAS G12C protein, promoted its degradation for up to 72 h, reduced cell viability, increased cell cycle arrest and promoted cell apoptosis. Mechanistic study found that the efficacy of PKD-1 was at least partially mediated by promoting 26S proteasome degradation process. Combined, these results extended previous findings and support the potential utility of PROTAC molecules such as PKD-1 as a new treatment strategy against pancreatic cancer.

Keywords
KRAS, KRAS G12C, PROTAC K-Ras Degrader-1, pancreatic cancer, apoptosis

Article Details

Supporting Agencies
This work was supported by the “Taishan Industry Leading Talent Laureate” and the “Major New Drugs Research & Development” special projects of Ministry of Science and Technology of PR China (No. 2018ZX09303015).
How to Cite
Gao, S., Zou, F., Zheng, L., Wang, Y., Feng, X., Liu, D., Mao, Y., Ye, L., & Tian, J. (2022). Efficacy and mechanism of KRAS G12C PROTAC in inhibiting the proliferation of pancreatic cancer cells. Journal of Pharmaceutical and Biopharmaceutical Research, 3(1), 176-184. https://doi.org/10.25082/JPBR.2021.01.002
Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

References

  1. Goral V. Pancreatic Cancer: Pathogenesis and Diagnosis. Asian Pacific Journal of Cancer Prevention, 2015, 16(14): 5619-5624. https://doi.org/10.7314/apjcp.2015.16.14.5619
  2. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science, 2008, 321(5897): 1801-1806. https://doi.org/10.1126/science.1164368
  3. Lippi G and Mattiuzzi C. The global burden of pancreatic cancer. Archives of Medical Science, 2020, 16(4): 820-824. https://doi.org/10.5114/aoms.2020.94845
  4. Park W, Chawla A and O’Reilly EM. Pancreatic cancer: a review. JAMA, 2021, 326(9): 851-862. https://doi.org/10.1001/jama.2021.13027
  5. American Cancer Society. Retrieved on December 12, 2021. https://www.cancer.org/cancer/pancreatic-cancer/detection-diagnosis-staging/survival-rates.html
  6. Lanfredini S, Thapa A and O’Neill E. RAS in pancreatic cancer. Biochemical Society Transactions, 2019, 47(4): 961-972. https://doi.org/10.1042/BST20170521
  7. Simanshu DK, Nissley DV and McCormick F. RAS Proteins and Their Regulators in Human Disease. Cell, 2017, 170(1): 17-33. https://doi.org/10.1016/j.cell.2017.06.009
  8. Rossman KL, Der CJ and Sondek J. GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nature Reviews Molecular Cell Biology, 2005, 6: 167-180. https://doi.org/10.1038/nrm1587
  9. Canon J, Rex K, Saiki AY, et al. The clinical KRAS (G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature, 2019, 575(7781): 217-223. https://doi.org/10.1038/s41586-019-1694-1
  10. Hallin J, Engstrom LD, Hargis L, et al. The KRAS (G12C) Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients. Cancer Discovery, 2020, 10(1): 54-71. https://doi.org/10.1158/2159-8290.CD-19-1167
  11. Bond MJ, Chu L, Nalawansha DA, et al. Targeted Degradation of Oncogenic KRAS (G12C) by VHL-Recruiting PROTACs. ACS Cent Sci, 2020, 6(8): 1367-1375. https://doi.org/10.1021/acscentsci.0c00411
  12. Paiva SL and Crews CM. Targeted protein degradation: elements of PROTAC design. Current Opinion in Chemical Biology, 2019, 50: 111-119. https://doi.org/10.1016/j.cbpa.2019.02.022
  13. Salami J and Crews CM. Waste disposal - An attractive strategy for cancer therapy. Science, 2017, 355(6330): 1163-1167. https://doi.org/10.1126/science.aam7340
  14. Lin X, Xiang H and Luo G. Targeting estrogen receptor α for degradation with PROTACs: A promising approach to overcome endocrine resistance. European Journal of Medicinal Chemistry, 2020, 206: 112689. https://doi.org/10.1016/j.ejmech.2020.112689
  15. Crew AP, Hornberger KR, Wang J, et al. Modulators of proteolysis and associated methods of use. WO2019/195609A2, 2019.
  16. Li DJ, Tong J, Zeng FY, et al. Nicotinic Ach alpha7 inhibits PDGF-induced migration of vascular smooth muscle cells by activating mitochondrial deacetylase sirtuin 3. British Journal of Pharmacology, 2019, 176(22): 4388-4401. https://doi.org/10.1111/bph.14506
  17. Wang HB, Ma XJ, Ren SM, et al. A small-molecule inhibitor of MDMX activates p53 and induces apoptosis. Molecular Cancer Therapeutics, 2011, 10(1): 69-79. https://doi.org/10.1158/1535-7163.MCT-10-0581
  18. Drosten M and Barbacid M. Targeting the MAPK Pathway in KRAS-Driven Tumors. Cancer Cell, 2020, 37(4): 543-550. https://doi.org/10.1016/j.ccell.2020.03.013
  19. Burslem GM and Crews CM. Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery. Cell, 2020, 181(1): 102-114. https://doi.org/10.1016/j.cell.2019.11.031