TY - JOUR
T1 - Assessing therapeutic efficacy of MEK inhibition in a KrasG12C-driven mouse model of lung cancer
AU - Li, Shuai
AU - Liu, Shengwu
AU - Deng, Jiehui
AU - Akbay, Esra A.
AU - Hai, Josephine
AU - Ambrogio, Chiara
AU - Zhang, Long
AU - Zhou, Fangyu
AU - Jenkins, Russell W.
AU - Adeegbe, Dennis O.
AU - Gao, Peng
AU - Wang, Xiaoen
AU - Paweletz, Cloud P.
AU - Herter-Sprie, Grit S.
AU - Chen, Ting
AU - Gutierrez-Quiceno, Laura
AU - Zhang, Yanxi
AU - Merlino, Ashley A.
AU - Quinn, Max M.
AU - Zeng, Yu
AU - Yu, Xiaoting
AU - Liu, Yuting
AU - Fan, Lichao
AU - Aguirre, Andrew J.
AU - Barbie, David A.
AU - Yi, Xianghua
AU - Wong, Kwok Kin
N1 - Funding Information:
We would like to acknowledge the help of Mei Zheng (Brigham and Women's Hospital) in immunohistochemistry studies. This work was supported by the National Cancer Institute R01 CA195740, CA205150, CA166480, CA140594, P01 CA154303, U01 CA213333 (to K.-K. Wong). This work was also funded by the National Natural Science Foundation of China (81401882, 81570053, and 81600043) and Key Medical Research of Shanghai (034119868 and 09411951600; to X.Y.). G.S. Herter-Sprie acknowledges funding from the Deutsche Forschungsgemeinschaft (HE 6897/1-1) and the Claudia Adams Barr Program for Innovative Cancer Research.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - Purpose: Despite the challenge to directly target mutant KRAS due to its high GTP affinity, some agents are under development against downstream signaling pathways, such as MEK inhibitors. However, it remains controversial whether MEK inhibitors can boost current chemotherapy in KRAS-mutant lung tumors in clinic. Considering the genomic heterogeneity among patients with lung cancer, it is valuable to test potential therapeutics in KRAS mutation-driven mouse models. Experimental Design: We first compared the pERK1/2 level in lung cancer samples with different KRAS substitutions and generated a new genetically engineered mouse model whose tumor was driven by KRASG12C, the most common KRAS mutation in lung cancer. Next, we evaluated the efficacy of selumetinib or its combination with chemotherapy, in KRASG12C tumors compared with KRASG12D tumors. Moreover, we generated KRASG12C/ p53R270H model to explore the role of a dominant negative p53 mutation detected in patients in responsiveness to MEK inhibition. Results: We determined higher pERK1/2 in KRASG12C lung tumors compared with KRASG12D. Using mouse models, we further identified that KRASG12C tumors are significantly more sensitive to selumetinib compared with KrasG12D tumors. MEK inhibition significantly increased chemotherapeutic efficacy and progression-free survival of KRASG12C mice. Interestingly, p53 co-mutation rendered KRASG12C lung tumors less sensitive to combination treatment with selumetinib and chemotherapy. Conclusions: Our data demonstrate that unique KRAS mutations and concurrent mutations in tumor-suppressor genes are important factors for lung tumor responses to MEK inhibitor. Our preclinical study supports further clinical evaluation of combined MEK inhibition and chemotherapy for lung cancer patients harboring KRASG12C and wild-type p53 status.
AB - Purpose: Despite the challenge to directly target mutant KRAS due to its high GTP affinity, some agents are under development against downstream signaling pathways, such as MEK inhibitors. However, it remains controversial whether MEK inhibitors can boost current chemotherapy in KRAS-mutant lung tumors in clinic. Considering the genomic heterogeneity among patients with lung cancer, it is valuable to test potential therapeutics in KRAS mutation-driven mouse models. Experimental Design: We first compared the pERK1/2 level in lung cancer samples with different KRAS substitutions and generated a new genetically engineered mouse model whose tumor was driven by KRASG12C, the most common KRAS mutation in lung cancer. Next, we evaluated the efficacy of selumetinib or its combination with chemotherapy, in KRASG12C tumors compared with KRASG12D tumors. Moreover, we generated KRASG12C/ p53R270H model to explore the role of a dominant negative p53 mutation detected in patients in responsiveness to MEK inhibition. Results: We determined higher pERK1/2 in KRASG12C lung tumors compared with KRASG12D. Using mouse models, we further identified that KRASG12C tumors are significantly more sensitive to selumetinib compared with KrasG12D tumors. MEK inhibition significantly increased chemotherapeutic efficacy and progression-free survival of KRASG12C mice. Interestingly, p53 co-mutation rendered KRASG12C lung tumors less sensitive to combination treatment with selumetinib and chemotherapy. Conclusions: Our data demonstrate that unique KRAS mutations and concurrent mutations in tumor-suppressor genes are important factors for lung tumor responses to MEK inhibitor. Our preclinical study supports further clinical evaluation of combined MEK inhibition and chemotherapy for lung cancer patients harboring KRASG12C and wild-type p53 status.
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U2 - 10.1158/1078-0432.CCR-17-3438
DO - 10.1158/1078-0432.CCR-17-3438
M3 - Article
C2 - 29945997
AN - SCOPUS:85054085161
SN - 1078-0432
VL - 24
SP - 4854
EP - 4864
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -