Mutant RAS Calms Stressed-Out Cancer Cells

Abstract

Mutant RAS-driven cancers are infamously resistant to chemotherapeutics. Reporting in Cell, Grabocka and Bar-Sagi (2016) demonstrate that when subjected to stress, mutant KRAS-dependent lipid production leads to upregulated stress granule formation. This confers not only cell-autonomous cytoprotection but also paracrine establishment of a stress-resistant tumor niche.

Figure 1. Mutant RAS Regulation of Stress Granule Formation and Resistance to Chemotherapy

(A) Mutant RAS activation of the RAF-MEK-ERK MAPK cascade promotes COX-2 upregulation and HPGD downregulation, stimulating an increase in 15-d-PGJ2. 15-d-PGJ2 then inactivates eIF4A, causing reduced ribosome initiation of translation, resulting in the accumulation of translationally stalled messenger ribo-nucleoprotein particles (mRNPs) containing exposed mRNA regions. This mRNA then binds SG-nucleating RNA-binding proteins, leading to the formation of stress granules (SGs). SGs also recruit signaling components that then drive resistance to chemotherapy. Treatment with either a MEK (MEKi) or COX (COXi) inhibitor blocked the stress-induced increase in SGs. Arrows indicate those activities that were linked to RAS activity. (B) RAS WT cancer cells express low levels of 15-d-PGJ2 and have low SG formation. When subjected to chemotherapy, RAS WT cancers are sensitive. In contrast, RAS-MUT cancer cells exhibit elevated 15-d-PGJ2 production and SG formation. 15-d-PGJ2 is also secreted and taken up by adjacent RAS WT cancer cells stimulating SG formation. When subjected to chemotherapy, both the RAS-MUT and WT cancers are chemoresistant. Treatments of RAS-MUT cancers with inhibitors of 15-d-PGJ2 expression or activity, preventing SG formation or function, are therapeutic strategies that may overcome this resistance and allow response to chemotherapy.