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Importance of the type I insulin-like growth factor receptor in HER2, FGFR2 and MET-unamplified gastric cancer with and without Ras pathway activation

Lookup NU author(s): Marina Saisana, Professor Michael Griffin, Dr Felicity May

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

Amplification of seven oncogenes: HER2, EGFR, FGFR1, FGFR2, MET, KRAS and IGF1R has been identified in gastric cancer. The first five are targeted therapeutically in patients with HER2-positivity, FGFR2- or MET-amplification but the majority of patients are triple-negative and require alternative strategies. Our aim was to evaluate the importance of the IGF1R tyrosine kinase in triple-negative gastric cancer with and without oncogenic KRAS, BRAF or PI3K3CA mutations. Cell lines and metastatic tumor cells isolated from patients expressed IGF1R, and insulin-like growth factor-1 (IGF-1) activated the PI3-kinase/Akt and Ras/Raf/MAP-kinase pathways. IGF-1 protected triple-negative cells from caspase-dependent apoptosis and anoikis. Protection was mediated via the PI3-kinase/Akt pathway. Remarkably, IGF-1-dependent cell survival was greater in patient samples. IGF-1 stimulated triple-negative gastric cancer cell growth was prevented by IGF1R knockdown and Ras/Raf/MAP-kinase pathway inhibition. The importance of the receptor in cell line and metastatic tumor cell growth in serum-containing medium was demonstrated by knockdown and pharmacological inhibition with figitumumab. The proportions of cells in S-phase and mitotic-phase, and Ras/Raf/MAP-kinase pathway activity, were reduced concomitantly. KRAS-addicted and BRAF-impaired gastric cancer cells were particularly susceptible. In conclusion, IGF1R and the IGF signal transduction pathway merit consideration as potential therapeutic targets in patients with triple-negative gastric cancer.

Publication metadata

Author(s): Saisana M, Griffin SM, May FEB

Publication type: Article

Publication status: Published

Journal: Oncotarget

Year: 2016

Volume: 7

Issue: 34

Pages: 54445-54462

Online publication date: 17/07/2016

Acceptance date: 14/05/2016

Date deposited: 03/05/2017

ISSN (electronic): 1949-2553

Publisher: Impact Journal LLC

URL: http://dx.doi.org/10.18632/oncotarget.10642

DOI: 10.18632/oncotarget.10642

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