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Importance of the type I insulin-like growth factor receptor in HER2, FGFR2 and MET-unamplified gastric cancer with

Marina Saisana1, S Michael Griffin1,2, Felicity E B May1,3

  • 1Northern Institute for Cancer Research, Newcastle upon Tyne Hospitals NHS Foundation Trust, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.

Oncotarget
|July 21, 2016
PubMed

Insights

Insulin-like growth factor 1 receptor (IGF1R) is crucial in triple-negative gastric cancer. Targeting IGF1R and its pathways shows promise for treating this aggressive cancer subtype.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Gastric cancer often involves oncogene amplification, including HER2, EGFR, FGFR1/2, MET, KRAS, and IGF1R.
  • Current therapies target HER2, FGFR2, or MET amplifications, leaving a majority of triple-negative gastric cancer patients with unmet needs.
  • The role of Insulin-like Growth Factor 1 Receptor (IGF1R) in triple-negative gastric cancer, particularly with common mutations, requires further investigation.

Purpose of the Study:

  • To evaluate the significance of the IGF1R tyrosine kinase in triple-negative gastric cancer.
  • To investigate the role of IGF1R in gastric cancer cells with and without KRAS, BRAF, or PI3K3CA mutations.
  • To assess the therapeutic potential of targeting IGF1R in this patient population.

Main Methods:

  • Analysis of IGF1R expression in gastric cancer cell lines and patient-derived metastatic tumor cells.
  • Investigated the activation of PI3-kinase/Akt and Ras/Raf/MAP-kinase pathways by insulin-like growth factor-1 (IGF-1).
  • Utilized IGF1R knockdown and pharmacological inhibition (figitumumab) to assess effects on cell survival, proliferation, and pathway activity.

Main Results:

  • IGF1R and IGF-1 activate key survival pathways (PI3-kinase/Akt, Ras/Raf/MAP-kinase) in triple-negative gastric cancer cells.
  • IGF-1 promotes cell survival by inhibiting apoptosis and anoikis, primarily through the PI3-kinase/Akt pathway.
  • IGF1R inhibition reduced cell proliferation, S-phase/mitotic-phase fractions, and Ras/Raf/MAP-kinase activity, with notable susceptibility in KRAS-mutated cells.

Conclusions:

  • IGF1R plays a critical role in the survival and growth of triple-negative gastric cancer.
  • The IGF signal transduction pathway represents a promising therapeutic target for triple-negative gastric cancer.
  • Targeting IGF1R may offer a viable strategy for patients with limited treatment options.
Keywords:
BRAF-impairedKRAS-addictedcell survival and proliferationgastric cancertype I IGF receptor

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