Targeting RAS-regulated stress granules in drug resistance in myeloma
Summary
PROJECT SUMMARY/ABSTRACT
Multiple myeloma (MM) is a life-threatening cancer of the blood and lymph system that is fatal for the majority of those diagnosed, accounting for more than 10% of all hematologic cancers. NRAS and KRAS mutations activate the RAS/RAF/MEK/ERK pathway in approximately 50% of MM cases. Stress granules (SGs) are non-membranous structures composed of mRNA, ribosomal proteins, and RNA-binding proteins that form in response to different stress stimuli and chemotherapeutic treatment. The KRAS effector pathway mediates the upregulation of SGs, conferring resistance to chemotherapeutic agents in solid tumors. However, the function of mutant KRAS-mediated SGs in MM pathobiology and chemotherapeutic resistance is not clear. We have recently shown that blocking this pathway with MEK1/2 inhibitors is a therapeutic option, but the response rate in MM varies from 30%–50%. Our studies demonstrate that the co-occurrence of t(14;16)/C-MAF overexpression confers resistance to the MEK inhibition, while RAS mutant cells alone are sensitive to MEK inhibition. We further discovered that the co-occurrence of t(14;16)/C-MAF in KRAS, NRAS, and BRAF mutant MM cells induces resistance to the MEK inhibitor, but RAS mutant cells alone are sensitive to MEK inhibition. It is not clear what causes patients with RAS mutations to be resistant to MEK inhibition. Thus, we hypothesize that mutant RAS-driven activation of the MEK/ERK cascades upregulates COX2, stimulating 15d-PGJ2 production; 15d-PGJ2 then inactivates elF4A to induce SG formation and recruit signaling components that drive resistance to chemotherapy. We propose that the interplay between mutant RAS and C-MAFplays a key role in SG formation, intersecting at the activation of MAPK to enhance MM cell survival and make RAS-mutant MM cells resistant to MEK-inhibitor therapy. We will use genetic approaches to address, for the first time, the mechanism by which SGs affect MM biology in the context of chemotherapy resistance. We have also developed cell models that permit us to investigate the molecular mechanisms of MM. Our ultimate goal is to identify new therapeutic targets for treating patients with high-risk disease with personalized, precision-medicine therapy. Our results will provide a foundation for developing therapeutic strategies that target RAS-regulated, SG-mediated resistance to chemotherapy to treat MM and improve outcomes for patients with RAS mutation. Our results will also offer insights about drug resistance in other types of blood cancers and solid tumor malignancies with RAS mutations and provide a strategy for developing new drugs targeted at SG-mediated drug resistance in RAS-mutant cancer.
Researchers:
- Ya-Wei Qiang (Author)
- HONG-YU Li
- Donald Johann