Wild-type RAS signaling is an essential therapeutic target in RAS-mutated cancers

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Mutated RAS proteins are key drivers of oncogenic transformation and cancer progression.
• RAS effector pathways, including RAF-MEK-ERK and PI3K-AKT, are differentially engaged by RAS family members.
• Effective treatment of RAS-mutated cancers often requires combined inhibition of these effector pathways.

Purpose of the Study:

• To elucidate the role of wild-type RAS proteins in supporting oncogenic signaling driven by mutant RAS.
• To investigate the therapeutic potential of cotargeting mutant RAS and its supporting wild-type RAS family members.
• To identify specific inhibitor combinations that achieve synergistic cytotoxicity in RAS-mutated cancers.

Main Methods:

• Investigated signaling interactions between mutant and wild-type RAS family members in cancer cells.
• Utilized specific inhibitors targeting mutant RAS proteins and their downstream effector pathways (e.g., MEK, PI3K inhibitors, farnesyltransferase inhibitor tipifarnib).
• Assessed synergistic cytotoxicity in cancer cell lines and genetically modified mouse embryonic fibroblasts (MEFs) lacking RAS proteins.

Main Results:

• Wild-type RAS proteins provide essential signaling support to mutant RAS pathways.
• Wild-type KRAS and NRAS promote RAF-MEK-ERK signaling in HRAS-mutated cells; wild-type HRAS and NRAS promote PI3K-AKT signaling in KRAS-mutated cells.
• Combined inhibition of mutant RAS and the poorly engaged effector pathway, dependent on wild-type RAS expression, resulted in synergistic cytotoxicity.

Conclusions:

• Wild-type RAS family members play a critical role in sustaining mutant RAS-driven oncogenic signaling.
• Targeting wild-type RAS proteins in combination with mutant RAS inhibitors represents a promising therapeutic strategy for RAS-mutated cancers.
• The dependency on wild-type RAS expression highlights its importance as a potential therapeutic cotarget.