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

Bin Yang, Xi Li, Yu Fu, Ensong Guo, Youqiong Ye, Fuxia Li, Si Liu, Rourou Xiao, Chen Liu, Funian Lu, Jia Huang, Tianyu Qin, Leng Han, Guang Peng, Gordon B. Mills, Chaoyang Sun, Gang Chen

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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 PARP 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 myeloidderived suppressor cell infiltration, in part, by inhibiting IL6 and GMCSF production. Importantly, addition of MEKi to PARPi and anti-PD-L1 resulted in marked tumor inhibition in immunocompetent mutant KRAS tumor models. This study provides the underlying mechanistic data to support evaluation of PARPi, MEKi, and anti-PD-L1 combination in clinical trials of mutant KRAS tumors.

    Original languageEnglish (US)
    Pages (from-to)2714-2729
    Number of pages16
    JournalCancer Research
    Volume81
    Issue number10
    DOIs
    StatePublished - May 2021

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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