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Clin Cancer Res. 2018 Oct 1;24(19):4854-4864. doi: 10.1158/1078-0432.CCR-17-3438. Epub 2018 Jun 26.

Assessing Therapeutic Efficacy of MEK Inhibition in a KRASG12C-Driven Mouse Model of Lung Cancer.

Author information

1
Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
2
Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
3
Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; Simmons Comprehensive Cancer Center, Dallas, Texas.
4
Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
5
Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
6
Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
7
Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York.
8
Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China. Kwok-Kin.Wong@nyumc.org yixhxf@163.com.
9
Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York. Kwok-Kin.Wong@nyumc.org yixhxf@163.com.
#
Contributed equally

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 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 KRAS G12C and wild-type p53 status. Clin Cancer Res; 24(19); 4854-64. ©2018 AACR.

PMID:
29945997
PMCID:
PMC6482448
DOI:
10.1158/1078-0432.CCR-17-3438
[Indexed for MEDLINE]
Free PMC Article

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