Trametinib overcomes KRAS-G12V-induced osimertinib resistance in a leptomeningeal carcinomatosis model of EGFR-mutant lung cancer.

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Tytuł:: Trametinib overcomes KRAS-G12V-induced osimertinib resistance in a leptomeningeal carcinomatosis model of EGFR-mutant lung cancer.
Autorzy:: Fukuda K; Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.; Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.
Otani S; Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.; Department of Respiratory Medicine, Kitasato University School of Medicine, Kanagawa, Japan.
Takeuchi S; Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.; Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.
Arai S; Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Nanjo S; Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.; Department of Medicine, Division of Hematology-Oncology, University of California San Francisco, San Francisco, CA, USA.
Tanimoto A; Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Nishiyama A; Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Naoki K; Department of Respiratory Medicine, Kitasato University School of Medicine, Kanagawa, Japan.
Yano S; Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.; Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.
Źródło:: Cancer science [Cancer Sci] 2021 Sep; Vol. 112 (9), pp. 3784-3795. Date of Electronic Publication: 2021 Jul 22.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Publication: 2005- : Oxford : Wiley Publishing on behalf of the Japanese Cancer Association
Original Publication: Tokyo : Japanese Cancer Association, c2003-
MeSH Terms:: Mutation*
Acrylamides/*administration & dosage
Aniline Compounds/*administration & dosage
Antineoplastic Agents/*administration & dosage
Carcinoma, Non-Small-Cell Lung/*drug therapy
Codon/*genetics
Drug Resistance, Neoplasm/*drug effects
Lung Neoplasms/*drug therapy
Meningeal Carcinomatosis/*drug therapy
Protein Kinase Inhibitors/*administration & dosage
Proto-Oncogene Proteins p21(ras)/*genetics
Pyridones/*administration & dosage
Pyrimidinones/*administration & dosage
Animals ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cell Survival/genetics ; Drug Resistance, Neoplasm/genetics ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Male ; Meningeal Carcinomatosis/genetics ; Meningeal Carcinomatosis/metabolism ; Mice ; Mice, SCID ; Proto-Oncogene Proteins p21(ras)/metabolism ; Pyridones/pharmacology ; Pyrimidinones/pharmacology ; Transfection ; Treatment Outcome ; Xenograft Model Antitumor Assays
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Grant Information:: 17K09649 Japan Society for the Promotion of Science; 18K07261 Japan Society for the Promotion of Science; 19H03665 Japan Society for the Promotion of Science; 20K17213 Japan Society for the Promotion of Science
Contributed Indexing:: Keywords: epidermal growth factor receptor; leptomeningeal carcinomatosis; non-small cell lung cancer; osimertinib; trametinib
Substance Nomenclature:: 0 (Acrylamides)
0 (Aniline Compounds)
0 (Antineoplastic Agents)
0 (Codon)
0 (KRAS protein, human)
0 (Protein Kinase Inhibitors)
0 (Pyridones)
0 (Pyrimidinones)
33E86K87QN (trametinib)
3C06JJ0Z2O (osimertinib)
EC 2.7.10.1 (EGFR protein, human)
EC 2.7.10.1 (ErbB Receptors)
EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
Entry Date(s):: Date Created: 20210619 Date Completed: 20210914 Latest Revision: 20220603
Update Code:: 20240104
PubMed Central ID:: PMC8409422
DOI:: 10.1111/cas.15035
PMID:: 34145930
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Leptomeningeal carcinomatosis (LMC) occurs frequently in non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and is associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, the mechanism by which LMC acquires resistance to osimertinib, a third-generation EGFR-TKI, is unclear. In this study, we elucidated the resistance mechanism and searched for a novel therapeutic strategy. We induced osimertinib resistance in a mouse model of LMC using an EGFR-mutant NSCLC cell line (PC9) via continuous oral osimertinib treatment and administration of established resistant cells and examined the resistance mechanism using next-generation sequencing. We detected the Kirsten rat sarcoma (KRAS)-G12V mutation in resistant cells, which retained the EGFR exon 19 deletion. Experiments involving KRAS knockdown in resistant cells and KRAS-G12V overexpression in parental cells revealed the involvement of KRAS-G12V in osimertinib resistance. Cotreatment with trametinib (a MEK inhibitor) and osimertinib resensitized the cells to osimertinib. Furthermore, in the mouse model of LMC with resistant cells, combined osimertinib and trametinib treatment successfully controlled LMC progression. These findings suggest a potential novel therapy against KRAS-G12V-harboring osimertinib-resistant LMC in EGFR-mutant NSCLC.
(© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

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