Targeting IRS-1/2 in Uveal Melanoma Inhibits In Vitro Cell Growth, Survival and Migration, and In Vivo Tumor Growth

Chandrani Chattopadhyay, Rajat Bhattacharya, Jason Roszik, Fatima S. Khan, Gabrielle A. Wells, Hugo Villanueva, Yong Qin, Rishav Bhattacharya, Sapna P. Patel, Elizabeth A. Grimm

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Uveal melanoma originating in the eye and metastasizing to the liver is associated with poor prognosis and has only one approved therapeutic option. We hypothesized that liver-borne growth factors may contribute to UM growth. Therefore, we investigated the role of IGF-1/IGF-1R signaling in UM. Here, we found that IRS-1, the insulin receptor substrate, is overexpressed in both UM cells and tumors. Since we previously observed that IGF-1R antibody therapy was not clinically effective in UM, we investigated the potential of NT157, a small molecule inhibitor of IRS-1/2, in blocking this pathway in UM. NT157 treatment of multiple UM cell lines resulted in reduced cell growth and migration and increased apoptosis. This treatment also significantly inhibited UM tumor growth in vivo, in the chicken egg chorioallantoic membrane (CAM) and subcutaneous mouse models, validating the in vitro effect. Mechanistically, through reverse phase protein array (RPPA), we identified significant proteomic changes in the PI3K/AKT pathway, a downstream mediator of IGF-1 signaling, with NT157 treatment. Together, these results suggest that NT157 inhibits cell growth, survival, and migration in vitro, and tumor growth in vivo via inhibiting IGF-1 signaling in UM.

Original languageEnglish (US)
Article number6247
JournalCancers
Volume14
Issue number24
DOIs
StatePublished - Dec 2022

Keywords

  • cell growth
  • cell migration
  • cell survival
  • in vivo models
  • insulin receptor substrates (IRS-1/2)
  • insulin-like growth factor (IGF-1) and its receptor (IGF-1R)
  • liver metastasis
  • NT157
  • tumor growth
  • uveal melanoma (UM)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Functional Proteomics Reverse Phase Protein Array Core
  • Bioinformatics Shared Resource
  • Flow Cytometry and Cellular Imaging Facility

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