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

Yinghui Zhang*, Lynn Wester, Jichao He, Tamar Geiger, Marja Moerkens, Ram Siddappa, Jean A. Helmijr, Mieke M. Timmermans, Maxime P. Look, Caroline H.M. Van Deurzen, John W.M. Martens, Chantal Pont, Marjo De Graauw, Erik H.J. Danen, Els M.J.J. Berns, John H.N. Meerman, Maurice P.H.M. Jansen, Bob Van De Water

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Antiestrogen resistance in estrogen receptor positive (ER + ) breast cancer is associated with increased expression and activity of insulin-like growth factor 1 receptor (IGF1R). Here, a kinome siRNA screen has identified 10 regulators of IGF1R-mediated antiestrogen with clinical significance. These include the tamoxifen resistance suppressors BMPR1B, CDK10, CDK5, EIF2AK1, and MAP2K5, and the tamoxifen resistance inducers CHEK1, PAK2, RPS6KC1, TTK, and TXK. The p21-activated kinase 2, PAK2, is the strongest resistance inducer. Silencing of the tamoxifen resistance inducing genes, particularly PAK2, attenuates IGF1R-mediated resistance to tamoxifen and fulvestrant. High expression of PAK2 in ER + metastatic breast cancer patients is correlated with unfavorable outcome after first-line tamoxifen monotherapy. Phospho-proteomics has defined PAK2 and the PAK-interacting exchange factors PIXα/β as downstream targets of IGF1R signaling, which are independent from PI3K/ATK and MAPK/ERK pathways. PAK2 and PIXα/β modulate IGF1R signaling-driven cell scattering. Targeting PIXα/β entirely mimics the effect of PAK2 silencing on antiestrogen re-sensitization. These data indicate PAK2/PIX as an effector pathway in IGF1R-mediated antiestrogen resistance.

Original languageEnglish
Pages (from-to)1869-1884
Number of pages16
JournalOncogene
Volume37
Issue number14
DOIs
StatePublished - 1 Apr 2018

Funding

FundersFunder number
Top Institute PharmaT3-107
KWF KankerbestrijdingUL-2011-5124

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