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Assessing Therapeutic Efficacy of MEK Inhibition in a KRASG12C-Driven Mouse Model of Lung Cancer
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Abstract
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 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. Clin Cancer Res; 24(19); 4854–64. ©2018 AACR.
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“studies with genetically engineered mouse model showed that KrasG12C tumors were significantly more sensitive to MEK inhibitor than the KrasG12D ones”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [17]
In the citing paper
“In KRAS-mutant lung cancer, tumors carrying KRASG12C exhibited higher ERK1/2 phosphorylation than those with KRASG12D (17).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [17]
In the citing paper
“Another study showed that presence of co-mutated Trp53 reduces sensitivity to combined treatment with MEK inhibitor and chemotherapy in KrasG12C-driven murine lung cancer”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [17]
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Metadata
- Authors
- Li, S., Liu, S., Deng, J., Akbay, E. A., Hai, J., Ambrogio, C., Zhang, L., Zhou, F., Jenkins, R. W., Adeegbe, D. O., Gao, P., Wang, X., Paweletz, C. P., Herter-Sprie, G. S., Chen, T., Gutiérrez-Quiceno, L., Zhang, Y., Merlino, A. A., Quinn, M. M., Zeng, Y., Yu, X., Liu, Y., Fan, L., Aguirre, A. J., Barbie, D. A., Yi, X., & Wong, K.-K.
- Affiliations
- Tongji University (CN)
- Harvard University (US)
- Harold C. Simmons Comprehensive Cancer Center (US)
- NYU Langone Health (US)
- Corresponding author
- Yi, Xianghua
- Wong, Kwok-Kin
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2018-10-01
- Volume
- 24
- Issue
- 19
- Pages
- 4854-4864
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC6482448
- OpenAlex
- W2811334006
- Cited by
- 67
- References
- 40
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 11 · 2023: 11 · 2022: 6 · 2021: 11 · 2020: 8 · 2019: 7 · 2018: 1
- FWCI
- 5.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- National Cancer Institute (R01 CA195740, CA205150, CA166480, CA140594, P01 CA154303, U01 CA213333)
- National Natural Science Foundation of China (81401882, 81570053, and 81600043)
- Medical Research of Shanghai (034119868 and 09411951600)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- KRAS G12C, MEK inhibition, selumetinib, lung cancer, KRAS G12D, combination chemotherapy, genetically engineered mouse models, tumor suppressor mutations, progression-free survival
- MeSH terms
- Animals, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Disease Models, Animal, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), MAP Kinase Signaling System, NIH 3T3 Cells, Cell Line, Tumor, Protein Kinase Inhibitors, MAP Kinase Kinase Kinase 1, Cell Proliferation, Mice, Allografts
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