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

Zhang, Y.; Wester, L.; He, J.; Geiger, T.; Moerkens, M.; Siddappa, R.; ... ; Water, B. van de (2018)

Article / Letter to editor

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.

• All authors: Zhang, Y.; Wester, L.; He, J.; Geiger, T.; Moerkens, M.; Siddappa, R.; Helmijr, J.A.; Timmermans, M.M.; Look, M.P.; Deurzen, C.H.M. van; Martens, J.W.M.; Pont, C.M.; Graauw, M. de; Danen, E.H.J.; Berns, E.M.J.J.; Jansen, M.P.H.M.; Meerman, J.H.N.; Water, B. van de
• Date: 2018-04-30
• Volume: 37
• Issue: 14
• Pages: 1869 - 1884
• DOI: doi:10.1038/s41388-017-0027-9