Elevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs.
There is a high death rate of lung cancer patients. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in some lung adenocarcinoma patients with EGFR mutations. However, a significant number of patients show primary and acquire resistance to EGFR-TKIs. Although the Akt kinase is commonly activated due to various resistance mechanisms, the key targets of Akt remain unclear. Here, we show that the Akt-β-catenin pathway may be a common resistance mechanism. We analyzed gene expression profiles of gefitinib-resistant PC9M2 cells that were derived from gefitinib-sensitive lung cancer PC9 cells and do not have known resistance mechanisms including EGFR mutation T790M. We found increased expression of Axin, a β-catenin target gene, increased phosphorylation of Akt and GSK3, accumulation of β-catenin in the cytoplasm/nucleus in PC9M2 cells. Both knockdown of β-catenin and treatment with a β-catenin inhibitor at least partially restored gefitinib sensitivity to PC9M2 cells. Lung adenocarcinoma tissues derived from gefitinib-resistant patients displayed a tendency to accumulate β-catenin in the cytoplasm. We provide a rationale for combination therapy that includes targeting of the Akt-β-catenin pathway to improve the efficacy of EGFR-TKIs.
1] Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University [2] Division of Molecular Therapy, Institute of Medical Science, University of Tokyo.
Asuka
A
Nakata
The Institute of Statistical Mathematics, 10-3 Midori-cho, Tachikawa Tokyo, 190-8562, Japan.
Ryo
R
Yoshida
Laboratory of Sequence Analysis, Institute of Medical Science, University of Tokyo.
Rui
R
Yamaguchi
Division of Molecular Therapy, Institute of Medical Science, University of Tokyo.
Mai
M
Yamauchi
Laboratory of DNA information Analysis, Institute of Medical Science, University of Tokyo.
Yoshinori
Y
Tamada
Laboratory of DNA information Analysis, Institute of Medical Science, University of Tokyo.
Andre
A
Fujita
Laboratory of DNA information Analysis, Institute of Medical Science, University of Tokyo.
Teppei
T
Shimamura
Laboratory of DNA information Analysis, Institute of Medical Science, University of Tokyo.
Seiya
S
Imoto
The Institute of Statistical Mathematics, 10-3 Midori-cho, Tachikawa Tokyo, 190-8562, Japan.
Tomoyuki
T
Higuchi
Department of Surgery, Tokyo Medical University.
Masaharu
M
Nomura
Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University.
Tatsuo
T
Kimura
Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital.
Hiroshi
H
Nokihara
Department of Thoracic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases.
Masahiko
M
Higashiyama
Department of Thoracic, Endocrine Surgery and Oncology, Institute of Health Bioscience, The University of Tokushima Graduate School.
Kazuya
K
Kondoh
Laboratory of Translational Pathology, Hokkaido University Graduate School of Medicine.
Hiroshi
H
Nishihara
Division of Molecular Therapy, Institute of Medical Science, University of Tokyo.
Arinobu
A
Tojo
Division of Medical Oncology, Cancer Research Institute, Kanazawa University.
Seiji
S
Yano
1] Laboratory of Sequence Analysis, Institute of Medical Science, University of Tokyo [2] Laboratory of DNA information Analysis, Institute of Medical Science, University of Tokyo.
Satoru
S
Miyano
1] Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University [2] Division of Molecular Therapy, Institute of Medical Science, University of Tokyo.
Noriko
N
Gotoh
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D020125:Mutation, Missense; D021381:Protein Transport; D011799:Quinazolines / Q000494:pharmacology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000502:physiology*
D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D011799:Quinazolines; D051176:beta Catenin; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib