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Differential Effects of IGF-1R Small Molecule Tyrosine Kinase Inhibitors BMS-754807 and OSI-906 on Human Cancer Cell

María Fuentes-Baile1, María P Ventero2, José A Encinar3

  • 1Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, 03203 Elche (Alicante), Spain.

Cancers
|December 16, 2020
PubMed

Insights

The insulin-like growth factor 1 receptor (IGF-1R) inhibitors BMS-754807 (BMS) and OSI-906 (OSI) showed differential effects on cancer cell proliferation. BMS demonstrated potent antiproliferative activity across multiple tumor types, suggesting broader therapeutic potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Insulin-like growth factor 1 receptor (IGF-1R) signaling plays a role in various cancers.
  • Targeting IGF-1R is a strategy for cancer therapy.
  • The differential effects of IGF-1R inhibitors require further investigation.

Purpose of the Study:

  • To evaluate the effects of IGF-1R tyrosine kinase inhibitors BMS-754807 (BMS) and OSI-906 (OSI) on cancer cell proliferation and cell cycle.
  • To compare the antiproliferative efficacy of BMS and OSI in human colon, pancreatic carcinoma, and glioblastoma cell lines.
  • To elucidate the mechanisms underlying the differential responses to these inhibitors.

Main Methods:

  • Treatment of human colon, pancreatic carcinoma, and glioblastoma cell lines and primary cultures with BMS and OSI.
  • Assessment of cell proliferation and cell-cycle phase distribution.
  • Analysis of effects on other protein kinases activities.

Main Results:

  • Both BMS and OSI effectively blocked IGF-1R signaling at equivalent doses.
  • BMS exhibited significant antiproliferative effects in pancreatic carcinoma and glioblastoma cell lines, while OSI had minimal impact.
  • BMS induced G2/M cell cycle arrest and subsequent cell death, whereas OSI induced G1 arrest without cell death, suggesting off-target effects of BMS on other kinases.

Conclusions:

  • BMS and OSI display differential antiproliferative effects on various cancer cell types.
  • BMS's potent anti-tumor activity may be attributed to off-target effects on other protein kinases.
  • BMS holds potential for treating diverse tumors, irrespective of their IGF-1R activation status.
Keywords:
ATP-binding domainIGF-1R inhibitorcolon carcinomaglioblastomamolecular dockingoff-target inhibitionpancreatic carcinomatyrosine kinase

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