Targeting Myc-driven stress vulnerability in mutant KRAS colorectal cancer (Ruan et al.)

Mutant KRAS is a key driver in colorectal cancer (CRC) and promotes Myc
translation and Myc-dependent stress adaptation and proliferation. Here,
we report that the combination of two FDA-approved drugs Bortezomib and
Everolimus (RAD001) (BR) is highly efficacious against mutant KRAS CRC
cells. Mechanistically, the combination, not single agent, rapidly
depletes Myc protein, not mRNA, and leads to GCN2- and p-eIF2a-dependent
cell death through the activation of extrinsic and intrinsic apoptotic
pathways. Cell death is selectively induced in mutant KRAS CRC cells with
elevated basal Myc and p-eIF2a and is characterized by CHOP induction and
transcriptional signatures in proteotoxicity, oxidative stress, metabolic
inhibition, and immune activation.  BR-induced p-GCN2/p-eIF2a
elevation and cell death are strongly attenuated by MYC knockdown and
enhanced by MYC overexpression. The BR combination is efficacious against
mutant KRAS patient derived organoids (PDO) and xenografts (PDX) by
inducing p-eIF2a/CHOP and cell death.  Interestingly, an elevated
four-gene (DDIT3, GADD45B, CRYBA4 and HSPA1L) stress signature is linked
to shortened overall survival in CRC patients. These data support that
Myc-dependent stress adaptation drives the progression of mutant KRAS CRC
and serves as a therapeutic vulnerability, which can be targeted using
dual translational inhibitors.