Inhibiting Scaffold-MAPK in Multiple Myeloma

Despite improved outcomes in newly diagnosed multiple myeloma (MM), virtually all patients relapse and ultimately develop drug-resistant disease. Aberrant RAS/MAPK signaling is activated in the majority of relapsed/refractory MM patients, but its biological consequences are not fully understood. Self-renewal, as defined by the long-term maintenance of clonogenic growth, is essential for disease relapse and we examined the role of RAS/MAPK activation on MM self-renewal by targeting IQ motif-containing GTPase activating protein 1 (IQGAP1), an intracellular scaffold protein required for mutant RAS signaling. We found that loss of IQGAP1 expression decreased MAPK signaling, cell cycle progression, and tumor colony formation. Similarly, a peptide mimicking the WW domain of IQGAP1 that interacts with ERK inhibited the clonogenic growth and self-renewal of MM cell lines and primary clinical specimens in vitro as well as tumor initiating cell frequency in immunodeficient mice. During MM progression, self-renewal may be enhanced by aberrant RAS/MAPK signaling and inhibited by targeting IQGAP1.

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