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IGF-1R inhibition induces schedule-dependent sensitization of human melanoma to temozolomide

Roger Ramcharan1, Tamara Aleksic1, Wilfride Petnga Kamdoum1

  • 1Department of Oncology, Old Road Campus Research Building, Oxford, UK.

Oncotarget
|October 27, 2015
PubMed

Insights

Combining IGF-1 receptor inhibitors with temozolomide (TMZ) enhances melanoma treatment. Optimal scheduling, with IGF-1 receptor inhibitors following TMZ, maximizes chemo-sensitization and tumor apoptosis, leading to significant growth delay.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Type 1 IGF receptor (IGF-1R) is implicated in chemo-resistance.
  • Temozolomide (TMZ) generates DNA adducts, with O6-methylguanine-DNA methyltransferase (MGMT) influencing its efficacy.
  • Melanoma resistance to TMZ may involve IGF-1R activation.

Purpose of the Study:

  • To investigate the influence of IGF-1R on response to temozolomide (TMZ) in melanoma.
  • To evaluate the efficacy of IGF-1R inhibitors (IGF-1Ri) in combination with TMZ.
  • To determine the optimal scheduling for combining IGF-1Ri with TMZ.

Main Methods:

  • Assessed correlation between TMZ resistance, MGMT expression, and phospho-IGF-1R in melanoma cell lines.
  • Tested effects of IGF-1Ri (AZ3801, linsitinib) on TMZ sensitivity, cell cycle, and DNA double-strand breaks (DSBs) in vitro.
  • Evaluated sequential TMZ → IGF-1Ri treatment in melanoma xenografts in mice.

Main Results:

  • TMZ resistance correlated with MGMT expression and IGF-1R activation in MGMT-proficient cell lines.
  • IGF-1Ri sensitized melanoma cells to TMZ independently of MGMT, with greater efficacy in wild-type p53 cells.
  • Sequential TMZ → IGF-1Ri treatment showed supra-additive tumor growth delay in vivo and enhanced intratumoral apoptosis.

Conclusions:

  • IGF-1R signaling contributes to TMZ resistance in melanoma.
  • Strategic scheduling of IGF-1Ri after TMZ is crucial for maximizing chemo-sensitization and therapeutic effect.
  • Combination therapy with optimal scheduling holds promise for melanoma treatment.
Keywords:
IGF-1Rapoptosischemo-sensitizationdouble strand breaktemozolomide

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