Li, Shuai, Liu, Shengwu, Deng, Jiehui ORCID: 0000-0001-7986-8643, Akbay, Esra A., Hai, Josephine ORCID: 0000-0002-5842-7686, Ambrogio, Chiara ORCID: 0000-0003-4122-701X, 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 and Wong, Kwok-Kin (2018). Assessing Therapeutic Efficacy of MEK Inhibition in a KRAS(G12C)-Driven Mouse Model of Lung Cancer. Clin. Cancer Res., 24 (19). S. 4854 - 4865. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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Abstract

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. (C) 2018 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Li, ShuaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, ShengwuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deng, JiehuiUNSPECIFIEDorcid.org/0000-0001-7986-8643UNSPECIFIED
Akbay, Esra A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hai, JosephineUNSPECIFIEDorcid.org/0000-0002-5842-7686UNSPECIFIED
Ambrogio, ChiaraUNSPECIFIEDorcid.org/0000-0003-4122-701XUNSPECIFIED
Zhang, LongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhou, FangyuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jenkins, Russell W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adeegbe, Dennis O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gao, PengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, XiaoenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paweletz, Cloud P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herter-Sprie, Grit S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, TingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gutierrez-Quiceno, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, YanxiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merlino, Ashley A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Quinn, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zeng, YuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yu, XiaotingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, YutingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fan, LichaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aguirre, Andrew J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barbie, David A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yi, XianghuaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wong, Kwok-KinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-171508
DOI: 10.1158/1078-0432.CCR-17-3438
Journal or Publication Title: Clin. Cancer Res.
Volume: 24
Number: 19
Page Range: S. 4854 - 4865
Date: 2018
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1557-3265
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SELUMETINIB PLUS DOCETAXEL; RECEPTOR TYROSINE KINASE; RANDOMIZED PHASE-II; CLINICAL-TRIAL; K-RAS; KRAS; ADENOCARCINOMA; RESISTANCE; EXPRESSION; MELANOMAMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17150

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