Strategies for Targeting KRAS: A Challenging Drug Target
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Abdul Wadood1, Amar Ajmal1, Ashfaq Ur Rehman2
1Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan 23200, KP, Pakistan.
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.
Insights
Targeting KRAS mutations, a leading cause of cancer, presents challenges due to protein similarity. New insights are driving the development of novel KRAS-targeted therapies for various cancers.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cancer remains a leading cause of death globally, with RAS family genes, particularly KRAS, NRAS, and HRAS, playing a significant role.
- KRAS mutations, especially in the KRAS4B isoform, are implicated in a substantial percentage of pancreatic, colon, and lung cancers, as well as rarer forms like liver and breast cancers.
Purpose of the Study:
- To review current strategies for targeting KRAS, a historically challenging cancer-driving protein.
- To highlight recent advancements and potential therapeutic avenues for KRAS-mutated cancers.
Main Methods:
- Literature review of scientific publications on KRAS structure, function, and therapeutic targeting strategies.
- Analysis of FDA-approved treatments and ongoing drug development for KRAS-driven malignancies.
Main Results:
- KRAS is the dominant mutant among RAS isoforms, driving a high proportion of RAS-related mutations.
- While sotorasib is approved for KRASG12C-mutated non-small cell lung cancer, other KRAS-driven cancers lack FDA-approved drugs.
- The structural similarity between mutant and wild-type KRAS proteins has historically made them 'undruggable'.
Conclusions:
- Despite historical challenges, new structural and functional insights into RAS proteins are enabling the development of promising drug candidates.
- Targeting KRAS represents a significant area of research with the potential to benefit patients with various difficult-to-treat cancers.
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