Identifying novel modes of oncogenic signaling in multiple myeloma

Division Of Basic Sciences - Nci

Investigators

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Abstract

The Young lab's research program is organized around two primary aims to address treatment resistance in multiple myeloma (MM). The first focus is on oncogenic RAS signaling, a key driver in up to 70% of relapsed/refractory cases. Our work has revealed that mutant RAS in MM uniquely co-opts endolysosomal machinery to activate the mTORC1 growth pathway. More recently, we identified novel regulators of RAS protein stability-the phosphatase PP1C, which promotes its degradation, and PAK kinases, which protect it-offering new avenues for therapeutic intervention. Building on these discoveries, we are assessing novel pan-RAS inhibitors, searching for synergistic drug combinations, and exploring the targeting of lysosome function as an alternative strategy to disrupt this pathogenic network. A second major effort employs a broad, unbiased proteogenomic strategy to uncover novel dependencies. Recognizing that genomic data alone has not yielded sufficient therapies, we are building a comprehensive functional map of gene essentialities using CRISPR screening across an extensive panel of MM cell lines, including unique models of advanced, treatment-refractory disease. A key success of this approach is the identification of the SWI/SNF chromatin remodeling complex as a critical vulnerability. We demonstrated that SWI/SNF activity is required to sustain the master transcription factor IRF4, and that its inhibition triggers a collapse of oncogenic networks driven by both IRF4 and MYC. This finding presents a powerful strategy for treating aggressive, IMiD-resistant MM and serves as the foundation for our ongoing proteogenomic screens to identify new vulnerabilities within the MYC oncogene network.