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

Tomoyasu Yoshihiro1, Hiroshi Ariyama2, Kyoko Yamaguchi2

  • 1Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Cancer Science
|September 2, 2022
PubMed

Insights

Microtubule targeting agents show limited efficacy in colorectal cancer (CRC). Targeting insulin-like growth factor 1 receptor (IGF-1R) signaling overcomes resistance to eribulin (Eri) in CRC, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Microtubule targeting agents (MTAs) are vital cancer treatments, but ineffective for colorectal cancer (CRC).
  • Preclinical data suggest BRAF-mutated CRC may respond to MTAs, yet clinical efficacy is limited for agents like eribulin (Eri).
  • Insulin-like growth factor 1 receptor (IGF-1R) signaling is implicated in resistance to cancer therapies.

Purpose of the Study:

  • To investigate the role of IGF-1R signaling in eribulin (Eri) resistance in colorectal cancer (CRC).
  • To determine if inhibiting IGF-1R can enhance the efficacy of Eri in CRC models.

Main Methods:

  • Utilized colorectal cancer (CRC) cell lines and a xenograft model.
  • Investigated the activation and nuclear translocation of insulin-like growth factor 1 receptor (IGF-1R) induced by eribulin (Eri).
  • Assessed the effects of inhibiting IGF-1R activation/translocation on Eri-induced DNA damage and cell cycle arrest.
  • Evaluated the combined efficacy of Eri and the IGF-1R inhibitor linsitinib in a xenograft model.

Main Results:

  • Eribulin (Eri) treatment activated and promoted nuclear translocation of insulin-like growth factor 1 receptor (IGF-1R) in CRC cells.
  • Inhibition of IGF-1R activation or nuclear translocation potentiated Eri-induced DNA damage and G2/M phase arrest.
  • Combination therapy with Eri and linsitinib significantly suppressed tumor growth in an Eri-resistant CRC xenograft model.

Conclusions:

  • Insulin-like growth factor 1 receptor (IGF-1R) signaling mediates resistance to eribulin (Eri) in colorectal cancer (CRC).
  • Combining eribulin (Eri) with an IGF-1R inhibitor represents a promising strategy to overcome treatment resistance in CRC.
  • This combination therapy offers a potential new therapeutic avenue for colorectal cancer patients.
Keywords:
IGF-1RROScolorectal cancereribulinmicrotubule

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