Classical RAS proteins are not essential for paradoxical ERK activation induced by RAF inhibitors

Area of Science:

• Molecular biology
• Cell signaling
• Cancer research

Background:

• RAF inhibitors are used in cancer therapy.
• Paradoxical ERK activation by RAF inhibitors is typically considered RAS-dependent.
• KRAS mutations are common in lung cancer.

Purpose of the Study:

• To investigate the role of classical RAS proteins in RAF inhibitor-induced paradoxical ERK signaling.
• To identify alternative pathways involved in RAF inhibitor-mediated ERK activation.

Main Methods:

• Utilized KRAS^G12C-dependent lung cancer cell lines and ARS1620 (a KRAS^G12C inhibitor).
• Employed H/N/KRAS-less mouse embryonic fibroblasts to assess RAS-independent signaling.
• Investigated the involvement of the MRAS/SHOC2 complex.

Main Results:

• Pan-RAF inhibitor LY3009120 induced paradoxical ERK activation in KRAS^G12C-dependent lung cancer cells treated with ARS1620.
• Classical RAS proteins (RAS) are not essential for RAF inhibitor-induced paradoxical ERK signaling.
• RAF inhibitors promote ERK phosphorylation, ERK target gene transcription, and cell proliferation in the absence of classical RAS.
• The MRAS/SHOC2 complex is required for this RAS-independent paradoxical ERK activation.

Conclusions:

• RAF inhibitor-induced paradoxical ERK signaling can occur independently of classical RAS proteins.
• The MRAS/SHOC2 complex plays a critical role in this alternative signaling pathway.
• This finding expands our understanding of RAF inhibitor allosteric regulation and identifies potential therapeutic targets beyond classical RAS.