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IGF1R signaling drives antiestrogen resistance through PAK2/PIX activation in luminal breast cancer

Yinghui Zhang1, Lynn Wester2, Jichao He2

  • 1Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands. y.zhang@lacdr.leidenuniv.nl.

Oncogene
|January 23, 2018
PubMed

Insights

Insulin-like growth factor 1 receptor (IGF1R) drives antiestrogen resistance in ER-positive breast cancer. The p21-activated kinase 2 (PAK2) pathway is identified as a key driver, suggesting new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Antiestrogen resistance limits treatment efficacy in estrogen receptor-positive (ER+) breast cancer.
  • Increased insulin-like growth factor 1 receptor (IGF1R) signaling is a known mechanism contributing to this resistance.

Purpose of the Study:

  • To identify key regulators of IGF1R-mediated antiestrogen resistance using a kinome siRNA screen.
  • To elucidate the role of identified regulators, particularly p21-activated kinase 2 (PAK2), in resistance mechanisms.
  • To investigate the downstream signaling of IGF1R in the context of antiestrogen resistance.

Main Methods:

  • Genome-wide kinome siRNA screen to identify regulators of IGF1R signaling.
  • Gene silencing experiments (siRNA) to assess the impact of identified regulators on tamoxifen and fulvestrant resistance.
  • Phospho-proteomics to define downstream signaling targets of IGF1R.
  • Analysis of patient data correlating gene expression with clinical outcomes.

Main Results:

  • A screen identified 10 regulators of IGF1R-mediated antiestrogen resistance, including suppressors and inducers.
  • p21-activated kinase 2 (PAK2) was identified as the strongest resistance inducer; its silencing sensitized cells to antiestrogens.
  • PAK2 and PAK-interacting exchange factors (PIXα/β) were identified as downstream IGF1R targets, independent of PI3K/Akt and MAPK/ERK pathways.
  • High PAK2 expression in ER+ metastatic breast cancer patients correlated with poor outcomes after tamoxifen therapy.

Conclusions:

  • The PAK2/PIX pathway is a critical effector in IGF1R-mediated antiestrogen resistance in ER+ breast cancer.
  • Targeting PAK2 or PIX demonstrates potential for overcoming antiestrogen resistance.
  • These findings highlight a novel therapeutic strategy for resistant ER+ breast cancer.

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