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Inhibition of RAS: proven and potential vulnerabilities
Mariyam Zuberi1,2, Imran Khan1,2, John P O'Bryan1,2
1Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, U.S.A.
Abstract:
RAS is a membrane localized small GTPase frequently mutated in human cancer. As such, RAS has been a focal target for developing cancer therapeutics since its discovery nearly four decades ago. However, efforts to directly target RAS have been challenging due to the apparent lack of readily discernable deep pockets for binding small molecule inhibitors leading many to consider RAS as undruggable. An important milestone in direct RAS inhibition was achieved recently with the groundbreaking discovery of covalent inhibitors that target the mutant Cys residue in KRAS(G12C). Surprisingly, these G12C-reactive compounds only target mutant RAS in the GDP-bound state thereby locking it in the inactive conformation and blocking its ability to couple with downstream effector pathways. Building on this success, several groups have developed similar compounds that selectively target KRAS(G12C), with AMG510 and MRTX849 the first to advance to clinical trials. Both have shown early promising results. Though the success with these compounds has reignited the possibility of direct pharmacological inhibition of RAS, these covalent inhibitors are limited to treating KRAS(G12C) tumors which account for <15% of all RAS mutants in human tumors. Thus, there remains an unmet need to identify more broadly efficacious RAS inhibitors. Here, we will discuss the current state of RAS(G12C) inhibitors and the potential for inhibiting additional RAS mutants through targeting RAS dimerization which has emerged as an important step in the allosteric regulation of RAS function.
Insights
Directly targeting RAS (Rat Sarcoma oncogene) proteins in cancer is challenging. Recent KRAS(G12C) inhibitors show promise but are limited; targeting RAS dimerization offers broader therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- RAS proteins are key regulators of cell signaling, frequently mutated in human cancers.
- Directly inhibiting RAS has been difficult due to its structure, leading to its classification as 'undruggable'.
- Targeting KRAS(G12C) mutations with covalent inhibitors represents a significant advancement in cancer therapy.
Purpose of the Study:
- To review the current landscape of KRAS(G12C) inhibitors.
- To explore novel strategies for inhibiting other RAS mutations.
- To highlight the potential of targeting RAS dimerization for broader cancer treatment.
Main Methods:
- Review of recent literature on RAS inhibitors.
- Analysis of the mechanism of action for KRAS(G12C) covalent inhibitors.
- Discussion of RAS dimerization as a therapeutic target.
Main Results:
- Covalent inhibitors targeting KRAS(G12C) are effective in preclinical and clinical studies.
- These inhibitors specifically target the GDP-bound state of KRAS(G12C).
- KRAS(G12C) mutations represent less than 15% of all RAS mutations in cancer.
Conclusions:
- While KRAS(G12C) inhibitors offer a breakthrough, they have limited applicability.
- Targeting RAS dimerization presents a promising avenue for developing inhibitors effective against a wider range of RAS mutations.
- Further research into RAS dimerization inhibitors is crucial for expanding therapeutic options in RAS-driven cancers.
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