Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated

To uncover novel RAS biology and potential therapeutic vulnerabilities, we employed a multi-omics screening approach in multiple myeloma to identify regulators of RAS activity. We report that the phosphatase PP1C dephosphorylates the conserved T148 residue on RAS, which in turn permits LZTR1-dependent proteasomal degradation.

Notably, LZTR1 is ineffective against KRAS A146 gain-of-function mutations, which are adjacent to T148 and prevalent in hematologic cancers, such as diffuse large B cell lymphoma and acute myeloid leukemia. Remarkably, we find that KRAS protein is four-fold less stable in hematologic versus carcinoma cells, offering a unique therapeutic opportunity targeting RAS protein stability mechanisms. The kinases PAK1 and PAK2 were shown to shield RAS from LZTR1-dependent degradation by phosphorylating T148, and targeting PAK1/2 activity improved RAS-directed therapy.