FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer.

Elevated expression of non-receptor tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/triple-negative breast cancer (TNBC) patients. Here, we show that high FER levels are also associated with improved outcomes after adjuvant taxane-based combination chemotherapy in high-risk, HER2-negative patients. In TNBC cells, we observe a causal relation between high FER levels and sensitivity to taxanes. Proteomics and mechanistic studies demonstrate that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identify DCTN2 as a FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for the development of tubular recycling domains in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for the benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients.

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Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

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Declaration of interests S.C.L. and H.M.O. received funding from Amgen, Sanofi, and the Dutch Cancer Society during the conduct of the study. S.C.L. reports grants and nonfinancial support from AstraZeneca, Genentech/Roche, Tesaro, and Immunomedics. S.C.L. received funding from Eurocept Pharmaceuticals, Novartis, and Pfizer and other support from Cergentis, IBM, Daiichi Sankyo, and Bayer outside the submitted work. S.C.L. is an advisory board member for Cergentis, IBM, Novartis, Pfizer, Roche, and Sanofi. H.M.O. is an advisory board member for Roche, Novartis, Pfizer, and MSD. J.K. received funding from Genentech/Roche. All other authors declare no competing interests.