Identifying novel modes of oncogenic signaling in multiple myeloma

Division Of Basic Sciences - Nci

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Abstract

To discover potential vulnerabilities to RAS signaling in MM, the Young lab employed unbiased proteogenomic screens to identify novel and unanticipated modes of oncogenic signaling in MM. We have performed whole-genome CRISPR-Cas9 screens to identify essential genes in 20 cell line models of MM. These screens confirmed the heterogeneous nature of this disease, as seen in the wide variation in essential genes between different MM lines. However, biological patterns emerged after MM lines were grouped by their dependency on KRAS or NRAS, the most mutated oncogenes in MM. To complement these genetic studies, we used quantitative mass spectrometry to determine the interactome of KRAS and NRAS in MM cells. The intersection of these genetics and proteomics datasets revealed surprising new insights into signaling in MM: we found that RAS isoforms directly stimulates mTORC1 activity in MM. mTORC1 integrates multiple signal inputs to balance cell growth and metabolism and is commonly deregulated in cancer. Current efforts in the lab are directed at elucidating the molecular mechanisms of mTORC1 activation by RAS and identifying molecular targets in this new pathway. Thus far, we have determined that RAS isoforms can essentially hijack the bioenergetic pathways feeding into mTORC1 activation. In addition to this, we are working to exploit this knowledge to design better treatments for MM. Targeting mTOR signaling as part of a combination therapy has worked well in clinical trials on lymphoma. To identify potential combination therapies in MM, we have performed CRISPR-Cas9 screens in MM lines treated with mTORC1 inhibitors along with high-throughput combinatorial drug screens. These screens revealed with that disrupting the MEK/ERK signaling cascade synergized with mTORC1 inhibition to kill MM cells.