TY - JOUR
T1 - MEK inhibition remodels the immune landscape of mutant kras tumors to overcome resistance to PARP and immune checkpoint inhibitors
AU - Yang, Bin
AU - Li, Xi
AU - Fu, Yu
AU - Guo, Ensong
AU - Ye, Youqiong
AU - Li, Fuxia
AU - Liu, Si
AU - Xiao, Rourou
AU - Liu, Chen
AU - Lu, Funian
AU - Huang, Jia
AU - Qin, Tianyu
AU - Han, Leng
AU - Peng, Guang
AU - Mills, Gordon B.
AU - Sun, Chaoyang
AU - Chen, Gang
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-20-2370
DO - 10.1158/0008-5472.CAN-20-2370
M3 - Article
C2 - 33589518
AN - SCOPUS:85105908460
SN - 0008-5472
VL - 81
SP - 2714
EP - 2729
JO - Cancer Research
JF - Cancer Research
IS - 10
ER -