Inhibition of insulin‐like growth factor‐1 receptor enhances eribulin‐induced DNA damage in colorectal cancer

Microtubule targeting agents (MTAs) such as taxanes are broadly used for the treatment of patients with cancer. Although MTAs are not effective for treatment of colorectal cancer (CRC), preclinical studies suggest that a subset of patients with CRC, especially those with cancers harboring the BRAF m...

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Bibliographic Details
Published in:Cancer science 2022-12, Vol.113 (12), p.4207-4218
Main Authors: Yoshihiro, Tomoyasu, Ariyama, Hiroshi, Yamaguchi, Kyoko, Imajima, Takashi, Yamaga, Satoru, Tsuchihashi, Kenji, Isobe, Taichi, Kusaba, Hitoshi, Akashi, Koichi, Baba, Eishi
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biomarkers
Cancer
Cell culture
Cell cycle
Cell Line, Tumor
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - genetics
Colorectal Neoplasms - metabolism
DNA Damage
Epidermal growth factor
eribulin
Flow cytometry
Humans
IGF‐1R
Insulin
Insulin-Like Growth Factor I
Insulin-like growth factors
Kinases
Laboratories
Localization
microtubule
Mutation
Nuclear transport
Original
ORIGINAL ARTICLES
Patients
Protein Kinase Inhibitors - pharmacology
Receptor, IGF Type 1 - antagonists & inhibitors
ROS
Tumors
Vinorelbine
Xenografts
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Summary:Microtubule targeting agents (MTAs) such as taxanes are broadly used for the treatment of patients with cancer. Although MTAs are not effective for treatment of colorectal cancer (CRC), preclinical studies suggest that a subset of patients with CRC, especially those with cancers harboring the BRAF mutation, could benefit from such agents. However, two MTAs, eribulin (Eri) and vinorelbine, have shown limited clinical efficacy. Here, we report that insulin‐like growth factor 1 receptor (IGF‐1R) signaling is involved in Eri resistance. Using CRC cell lines, we showed that Eri induces activation and subsequent translocation of IGF‐1R to the nucleus. When the activation and/or nuclear translocation of IGF‐1R was inhibited, Eri induced DNA damage and enhanced G2/M arrest. In a xenograft model using the Eri‐resistant SW480 cell line, the combination of Eri and the IGF‐1R inhibitor linsitinib suppressed tumor growth more efficiently than either single agent. Thus, our results indicated that combination dosing with Eri and an IGF‐1R inhibitor could overcome Eri resistance and offer a therapeutic opportunity in CRC. Nuclear translocation of IGF‐1R in SW480 following exposure to eribulin revealed by immunofluorescent staining. Nuclear translocation of IGF‐1R was not observed when exposed to the combination of eribulin and IGF‐1R inhibitor.
ISSN:1347-9032
1349-7006
1349-7006
DOI:10.1111/cas.15558