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Evasion mechanisms to Igf1r inhibition in rhabdomyosarcoma

Jinu Abraham1, Suresh I Prajapati, Koichi Nishijo

  • 1Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas, USA.

Molecular Cancer Therapeutics
|March 31, 2011
PubMed

Insights

Targeting the insulin-like growth factor 1 receptor (Igf1r) shows promise for alveolar rhabdomyosarcoma (ARMS). However, resistance can occur, suggesting a need to also target Her2 for improved treatment outcomes in this aggressive cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Metastatic alveolar rhabdomyosarcoma (ARMS) has a poor prognosis, prompting research into targeted therapies.
  • Inhibition of the insulin-like growth factor 1 receptor (Igf1r) is a strategy explored in clinical trials for ARMS.
  • Understanding mechanisms of Igf1r inhibitor resistance is crucial for effective treatment.

Purpose of the Study:

  • To investigate potential mechanisms of resistance to Igf1r inhibitors in ARMS.
  • To identify therapeutic strategies to overcome Igf1r inhibitor resistance in ARMS.

Main Methods:

  • Utilized a genetically engineered mouse model of ARMS with validated Igf1r signaling.
  • Administered the Igf1r inhibitor NVP-AEW541 in vitro and in vivo.
  • Analyzed drug resistance markers including Igf1r, Mapk, and Her2.
  • Investigated Her2-Igf1r heterodimerization and the effect of Her2 inhibition with lapatinib.

Main Results:

  • NVP-AEW541 inhibited ARMS cell growth and induced apoptosis in vitro by decreasing Akt and Mapk phosphorylation.
  • In vivo, resistance to NVP-AEW541 was observed, associated with Igf1r overexpression, Mapk reactivation, and Her2 overexpression.
  • Her2 formed heterodimers with Igf1r in resistant cells, and Igf2 stimulation led to Her2 phosphorylation.
  • The Her2 inhibitor lapatinib, in combination with NVP-AEW541, reduced Igf1r phosphorylation and inhibited cell growth.

Conclusions:

  • Igf1r inhibitor resistance in ARMS involves Igf1r overexpression, Mapk reactivation, and Her2 signaling.
  • Simultaneous targeting of Igf1r and Her2 may be a promising therapeutic strategy to overcome resistance in ARMS.

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