Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Oncogenic RAS mutations are prevalent in multiple myeloma (MM), a plasma cell malignancy.
• The precise mechanisms and therapeutic targets of RAS signaling in MM are not well understood.

Purpose of the Study:

• To elucidate the pathogenic mechanisms of RAS signaling in multiple myeloma.
• To identify novel therapeutic targets for MM by dissecting RAS signaling pathways.

Main Methods:

• Utilized an unbiased proteogenomic approach to analyze RAS signaling in MM.
• Investigated the interaction of RAS with other proteins and cellular pathways.

Main Results:

• Discovered that mutant RAS forms a signaling complex with SLC3A2 and MTOR on endolysosomes, activating mTORC1.
• Observed that high mTORC1 activity correlates with aggressive MM and RAS mutations.
• Detected RAS-MTOR interactions in patient tumors with mutant RAS.

Conclusions:

• Redefined the RAS pathway in MM, highlighting its role in activating mTORC1.
• Established a mechanistic basis for targeting RAS-dependent mTORC1 signaling in MM.
• Demonstrated synergistic effects of inhibiting RAS-dependent mTORC1 with MEK/ERK inhibitors.