Title:Strategies for Targeting KRAS: A Challenging Drug Target
Volume: 28
Issue: 23
Author(s): Abdul Wadood*, Amar Ajmal and Ashfaq Ur Rehman
Affiliation:
- Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan 23200, KP, Pakistan
Keywords:
KRAS oncogene, KRAS signalling, KRAS structure, targeted therapy, KRAS4B isoform, drug target.
Abstract: In the developed world, cancer is the most common cause of death. Among the 36 human genes of
the RAS family, KRAS, NRAS, and HRAS play a prominent role in human cancer. KRAS belongs to the Ras
superfamily of proteins and is a small GTPase signal transduction protein. Among the RAS isoform, KRAS is
the dominant mutant that induces approximately 86% of the RAS mutations. The most frequently mutated
KRAS isoform is KRAS4B. About 90% of pancreatic cancer, 30-40% of colon cancer, and 15 to 20% of lung
cancers are caused by mutations KRAS4B isoform. Liver cancer, bladder cancer, breast cancer, and myeloid
leukaemia are also caused by mutations in KRAS but are rare. The FDA has recently approved sotorasib for the
treatement of KRASG12C-mutated advanced non-small cell lung cancer (NSCLC) patients. However, no FDAapproved
drugs are available for other KRAS-driven cancer. As the KRAS proteins lack a druggable pocket accessible
to the chemical inhibitors, the cancer-causing mutant proteins are almost identical to their essential
wild-type counterparts. Therefore, they are considered undruggable. The new insights into the structure and
function of RAS have changed this understanding and encouraged the development of many drug candidates.
This review provides information about the different strategies for targeting KRAS, a challenging drug target
that might be valuable for the scientific community.
