Targeting ROR1 in combination with osimertinib in EGFR mutant lung cancer cells

Nozomu Nakagawa; Noriko Miyake; Nobuaki Ochi; Hiromichi Yamane; Masami Takeyama; Yasunari Nagasaki; Tomoko Ikeda; Etsuko Yokota; Takuya Fukazawa; Hidekazu Nakanishi; Daijiro Harada; Katsuyuki Kiura; Nagio Takigawa

doi:10.1016/j.yexcr.2021.112940

Targeting ROR1 in combination with osimertinib in EGFR mutant lung cancer cells

Exp Cell Res. 2021 Dec 15;409(2):112940. doi: 10.1016/j.yexcr.2021.112940. Epub 2021 Nov 19.

Affiliations

¹ Department of General Internal Medicine 4, Kawasaki Medical School, 2-6-1 Nakasange, Kita-ku, Okayama, 700-8505, Japan.
² General Medical Center Research Unit, Kawasaki Medical School, 2-6-1 Nakasange, Kita-ku, Okayama, 700-8505, Japan.
³ Department of General Surgery, Kawasaki Medical School, 2-6-1 Nakasange, Kita-ku, Okayama, 700-8505, Japan.
⁴ General Medical Center Research Unit, Kawasaki Medical School, 2-6-1 Nakasange, Kita-ku, Okayama, 700-8505, Japan; Department of General Surgery, Kawasaki Medical School, 2-6-1 Nakasange, Kita-ku, Okayama, 700-8505, Japan.
⁵ Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
⁶ Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
⁷ Department of General Internal Medicine 4, Kawasaki Medical School, 2-6-1 Nakasange, Kita-ku, Okayama, 700-8505, Japan; General Medical Center Research Unit, Kawasaki Medical School, 2-6-1 Nakasange, Kita-ku, Okayama, 700-8505, Japan. Electronic address: ntakigaw@gmail.com.

PMID: 34808132
DOI: 10.1016/j.yexcr.2021.112940

Abstract

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.

Keywords: EGFR; Lung cancer; Osimertinib; ROR1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acrylamides / pharmacology*
Aniline Compounds / pharmacology*
Animals
Antineoplastic Agents / pharmacology
Apoptosis
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / pathology
Carcinoma, Non-Small-Cell Lung / therapy*
Cell Proliferation
Combined Modality Therapy
Drug Resistance, Neoplasm*
ErbB Receptors / genetics
Humans
Lung Neoplasms / genetics
Lung Neoplasms / pathology
Lung Neoplasms / therapy
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Mutation*
RNA, Small Interfering / genetics*
Receptor Tyrosine Kinase-like Orphan Receptors / antagonists & inhibitors*
Receptor Tyrosine Kinase-like Orphan Receptors / genetics
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

Acrylamides
Aniline Compounds
Antineoplastic Agents
RNA, Small Interfering
osimertinib
EGFR protein, human
ErbB Receptors
ROR1 protein, human
Receptor Tyrosine Kinase-like Orphan Receptors