TY - JOUR
T1 - Targeting ROR1 in combination with osimertinib in EGFR mutant lung cancer cells
AU - Nakagawa, Nozomu
AU - Miyake, Noriko
AU - Ochi, Nobuaki
AU - Yamane, Hiromichi
AU - Takeyama, Masami
AU - Nagasaki, Yasunari
AU - Ikeda, Tomoko
AU - Yokota, Etsuko
AU - Fukazawa, Takuya
AU - Nakanishi, Hidekazu
AU - Harada, Daijiro
AU - Kiura, Katsuyuki
AU - Takigawa, Nagio
N1 - Funding Information:
This research was partially supported by Japanese pharmaceutical companies, including Takeda Pharmaceutical Company, Pfizer Inc., Boehringer-Ingelheim, Eli Lilly, Ono Pharmaceutical Co. Ltd, Chugai Pharmaceutical, and Nippon Kayaku Co. Ltd. Dr. Harada has received research funds from Eli Lilly Japan, MSD, Chugai Pharmaceutical, Pfizer Inc. Japan, Bristol-Myers Squibb Company Japan, AstraZeneca, Novartis Pharmaceuticals Japan, Kissei Pharmaceutical Co. Ltd. and Takeda Pharmaceutical Co. Ltd., personal fees from MSD, Ono Pharmaceutical, Bristol-Myers Squibb Company Japan, Kyowa Hakko Kirin, AstraZeneca, Boehringer-Ingelheim Japan, Towa Pharmaceutical Co. Ltd., Chugai Pharmaceutical, Taiho Pharmaceutical and Eli Lilly Japan outside the submitted work.
Funding Information:
This work was supported by a Research Project Grant ( 25–45 , 27–18 ) from Kawasaki Medical School , Japan, and by Grants-in-Aid for Scientific Research (KAKENHI) , Japan ( 21K08191 ).
Funding Information:
Dr. Kiura has received grants from Daiichi Sankyo Co., Ltd., Teijin Pharmaceutical Ltd., Pfizer Inc., Shionogi & Co., Ltd, Boehringer-Ingelheim Co. Ltd., Nippon Kayaku Co. Ltd., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd. Kyorin Pharmaceutical Co.,Ltd., MSD, Chugai Pharmaceutical, Bristol-Myers Squibb K.K. Merck Biopharma Co., Ltd, Takeda Pharmaceutical Co., Ltd.; personal fees from AstraZeneca, Eli Lilly Japan, Novartis International AG, Taiho Pharmaceutical Co., Ltd. Chugai Pharmaceutical Co., Ltd. Pfizer Japan Inc. Ono Pharmaceutical Co., Ltd. Bristol-Myers Squibb, MSD, Boehringer Ingelheim Co., Ltd. Daiichi Sankyo Co., Ltd. outside the submitted work.
Funding Information:
Dr. Takigawa has received grants and personal fees from Eli Lilly Japan, AstraZeneca, Daiichi-Sankyo Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer Inc. Japan, Boehringer-Ingelheim Japan, and Ono Pharmaceutical; grants from Kyowa Hakko Kirin, Nippon Kayaku Co. Ltd., and Takeda Pharmaceutical Co. Ltd.; and personal fees from MSD and Bristol-Myers Squibb Company Japan outside the submitted work. The other authors have no conflicts of interest to declare.
Funding Information:
Dr. Harada has received research funds from Eli Lilly Japan, MSD, Chugai Pharmaceutical, Pfizer Inc. Japan, Bristol-Myers Squibb Company Japan, AstraZeneca, Novartis Pharmaceuticals Japan, Kissei Pharmaceutical Co. Ltd. and Takeda Pharmaceutical Co. Ltd., personal fees from MSD, Ono Pharmaceutical, Bristol-Myers Squibb Company Japan, Kyowa Hakko Kirin, AstraZeneca, Boehringer-Ingelheim Japan, Towa Pharmaceutical Co. Ltd., Chugai Pharmaceutical, Taiho Pharmaceutical and Eli Lilly Japan outside the submitted work.
Funding Information:
Dr. Kiura has received grants from Daiichi Sankyo Co., Ltd., Teijin Pharmaceutical Ltd., Pfizer Inc., Shionogi & Co., Ltd, Boehringer-Ingelheim Co. Ltd., Nippon Kayaku Co. Ltd., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd. Kyorin Pharmaceutical Co.,Ltd., MSD, Chugai Pharmaceutical, Bristol-Myers Squibb K.K. Merck Biopharma Co., Ltd, Takeda Pharmaceutical Co., Ltd.; personal fees from AstraZeneca, Eli Lilly Japan, Novartis International AG, Taiho Pharmaceutical Co., Ltd. Chugai Pharmaceutical Co., Ltd. Pfizer Japan Inc. Ono Pharmaceutical Co., Ltd. Bristol-Myers Squibb, MSD, Boehringer Ingelheim Co., Ltd. Daiichi Sankyo Co., Ltd. outside the submitted work. Dr. Takigawa has received grants and personal fees from Eli Lilly Japan, AstraZeneca, Daiichi-Sankyo Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer Inc. Japan, Boehringer-Ingelheim Japan, and Ono Pharmaceutical; grants from Kyowa Hakko Kirin, Nippon Kayaku Co. Ltd., and Takeda Pharmaceutical Co. Ltd.; and personal fees from MSD and Bristol-Myers Squibb Company Japan outside the submitted work.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/12/15
Y1 - 2021/12/15
N2 - Lung cancer that exhibits epidermal growth factor receptor (EGFR) gene mutation is sensitive to EGFR-tyrosine kinase inhibitors (TKIs), such as osimertinib. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) may be involved in overcoming EGFR-TKI resistance. Growth inhibition, colony formation, apoptosis, and mRNA/protein levels in four osimertinib-sensitive and resistant cell lines transfected with small interfering RNA (siRNA) targeting ROR1 (siROR1) were evaluated. Cell growth and colony formation were suppressed and apoptosis was increased in all cell lines treated with siROR1. Although EGFR, AKT, and ERK phosphorylation were not suppressed in all cell lines, TGF-β2, AXL, CDH2, PARP1, PEG10, and TYMS mRNA expression levels were reduced. The combination of osimertinib with siROR1 was effective for the four cell lines, particularly in the two osimertinib-sensitive lines. In conclusion, targeting ROR1 in combination with osimertinib in EGFR mutant lung cancer may be a novel therapeutic option.
AB - Lung cancer that exhibits epidermal growth factor receptor (EGFR) gene mutation is sensitive to EGFR-tyrosine kinase inhibitors (TKIs), such as osimertinib. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) may be involved in overcoming EGFR-TKI resistance. Growth inhibition, colony formation, apoptosis, and mRNA/protein levels in four osimertinib-sensitive and resistant cell lines transfected with small interfering RNA (siRNA) targeting ROR1 (siROR1) were evaluated. Cell growth and colony formation were suppressed and apoptosis was increased in all cell lines treated with siROR1. Although EGFR, AKT, and ERK phosphorylation were not suppressed in all cell lines, TGF-β2, AXL, CDH2, PARP1, PEG10, and TYMS mRNA expression levels were reduced. The combination of osimertinib with siROR1 was effective for the four cell lines, particularly in the two osimertinib-sensitive lines. In conclusion, targeting ROR1 in combination with osimertinib in EGFR mutant lung cancer may be a novel therapeutic option.
KW - EGFR
KW - Lung cancer
KW - Osimertinib
KW - ROR1
UR - http://www.scopus.com/inward/record.url?scp=85119320241&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85119320241&partnerID=8YFLogxK
U2 - 10.1016/j.yexcr.2021.112940
DO - 10.1016/j.yexcr.2021.112940
M3 - Article
C2 - 34808132
AN - SCOPUS:85119320241
VL - 409
JO - Experimental Cell Research
JF - Experimental Cell Research
SN - 0014-4827
IS - 2
M1 - 112940
ER -
