Assessing Therapeutic Efficacy of MEK Inhibition in a KRAS(G12C)-Driven Mouse Model of Lung Cancer

作者：Li, Shuai; Liu, Shengwu; Deng, Jiehui; Akbay, Esra A.; Hai, Josephine; Ambrogio, Chiara; Zhang, Long; Zhou, Fangyu; Jenkins, Russell W.; Adeegbe, Dennis O.; Gao, Peng; Wang, Xiaoen; Paweletz, Cloud P.; Herter-Sprie, Grit S.; Chen, Ting; Gutierrez-Quiceno, Laura; Zhang, Yanxi; Merlino, Ashley A.; Quinn, M.; Zeng, Yu; Yu, Xiaoting; Liu, Yuting; Fan, Lichao; Aguirre, Andrew J.; Barbie, David A.; Yi, Xianghua^*; Wong, Kwok-Kin^*

来源：Clinical Cancer Research, 2018, 24(19): 4854-4864.

DOI：10.1158/1078-0432.CCR-17-3438

• SELUMETINIB PLUS DOCETAXEL
• RECEPTOR TYROSINE KINASE
• RANDOMIZED PHASE-II
• CLINICAL-TRIAL
• K-RAS
• KRAS
• ADENOCARCINOMA
• RESISTANCE
• EXPRESSION
• MELANOMA

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 KRAS(G12C), the most common KRAS mutation in lung cancer. Next, we evaluated the efficacy of selumetinib or its combination with chemotherapy, in KRAS(G12C) tumors compared with KRAS(G12D )tumors. Moreover, we generated KRAS(G12C)/ p53(R270H) 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 KRAS(G12C) lung tumors compared with KRAS(G12D). Using mouse models, we further identified that KRAS(G12C) tumors are significantly more sensitive to selumetinib compared with KRAS(G12D) tumors. MEK inhibition significantly increased chemotherapeutic efficacy and progression-free survival of KRAS(G12C )mice. Interestingly, p53 co-mutation rendered KRAS(G12C) 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 KRAS(G12C) and wild-type p53 status.

• 出版日期2018-10-1
• 单位同济大学