Identifying novel modes of oncogenic signaling in multiple myeloma

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

To discover potential vulnerabilities to RAS signaling in multiple myeloma, the Young lab employed unbiased proteogenomic screens to identify novel and unanticipated modes of oncogenic signaling in multiple myeloma. We have performed whole-genome CRISPR-Cas9 screens to identify essential genes in 20 cell line models of multiple myeloma. These screens confirmed the heterogeneous nature of this disease, as seen in the wide variation in essential genes between different multiple myeloma lines. However, biological patterns emerged after multiple myeloma lines were grouped by their dependency on KRAS or NRAS. To complement these genetic studies, we used quantitative mass spectrometry to determine the interactome of KRAS and NRAS in multiple myeloma cells. The intersection of these genetics and proteomics datasets revealed surprising new insights into signaling in multiple myeloma. We found that RAS isoforms directly stimulates mTORC1 activity in multiple myeloma. 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 amino acid transporters feeding into mTORC1 activation. In addition to this, we are working to exploit this knowledge to design better treatments for multiple myeloma. Targeting mTOR signaling as part of a combination therapy has worked well in clinical trials on lymphoma. To identify potential combination therapies in multiple myeloma, we have performed high-throughput combinatorial drug screens to identify drugs that have synergistic toxicity with mTORC1 inhibitors. These screens revealed with that disrupting the MEK/ERK signaling cascade synergized with mTORC1 inhibition to kill multiple myeloma cells harboring active RAS signaling, and may offer an alternative to stem cell transplants for patients with relapsed/refractory disease.