MEK inhibition remodels the immune landscape of mutant KRAS tumors to overcome resistance to PARP and immune checkpoint inhibitors

KRAS Protein Structure

KRAS Protein Structure \ Source: NCI

Yang B, Li X, Fu Y, Guo E, Ye Y, Li F, Liu S, Xiao R, Liu C, Lu F, Huang J, Qin T, Han L, Peng G, Mills GB, Sun C, Chen G.

Cancer Research

February 15, 2021

Mutant KRAS tumors are associated with poor outcomes at least in part due to decreased therapeutic sensitivity. Here we show that KRAS mutations are associated with resistance to monotherapy and combination therapy with Poly-(ADP-ribose) polymerase inhibitors (PARPi) and immune checkpoint blockade with anti-PD-L1 antibodies. In mutant KRAS tumors, inhibition of KRAS signaling with MEK inhibitors (MEKi) triggered and amplified PARPi-induced DNA damage, cytosolic double-stranded DNA accumulation, STING pathway activation and CD8+ T cell recruitment. Moreover, MEKi decreased myeloid-derived suppressor cell infiltration in part by inhibiting IL-6 and GM-CSF production. Importantly, addition of MEKi to PARPi and anti-PD-L1 resulted in marked tumor inhibition in immunocompetent mutant KRAS tumor models. These studies provide the underlying mechanistic data to support evaluation of PARPi, MEKi, and anti-PD-L1 combination in clinical trials of mutant KRAS tumors.

Last updated: April 13, 2021