HORMAD1 drives spindle assembly checkpoint defects and sensitivity to multiple mitotic kinases

Background: The study aimed to identify and target effects associated with HORMAD1 expression in breast cancer cells. Materials and methods: Isogenic cell line models with inducible HORMAD1 expression were used to identify dependencies induced by HORMAD1 expression. Results: Expression of HORMAD1, a gene whose function is best understood in meiosis, is usually restricted to germ-line cells but becomes aberrantly expressed in 60% of triple-negative breast cancers (TNBCs), where a clearly bimodal distribution of expression is associated with signatures of genomic instability. Here, we report that HORMAD1 expression in mitotic cells leads to defects in the spindle assembly checkpoint (SAC). These defects were observed despite functional MAD2-dependent SAC activity, and were instead a consequence of an interaction with and disruption of the chromosome passenger complex, leading to decreased Aurora B signalling. HORMAD1-driven SAC defects were also associated with excessive chromosome instability and cellular sensitivity to MPS1, Aurora B and BUB1 inhibitors, all of which are of great clinical interest in TNBC. Conclusions: Our data demonstrate that aberrant HORMAD1 expression in cancer leads to SAC defects, and highlights several therapeutic targets for a large subset of breast cancers that express HORMAD1. This may also be relevant in a wider group of high clinical need cancers that similarly demonstrate bimodal HORMAD1expression. Conflict of interest: Ownership: CJL has stock in: Tango, Ovibio, Enedra Tx., Hysplex ANJT has stock in: InBiomotion Advisory Board: CJL: Syncona, Sun Pharma, Gerson Lehrman Group, Merck KGaA, Vertex, AstraZeneca, Tango, 3rd Rock, Ono Pharma, Artios, Abingworth, Tesselate. ANJT: Pfizer, Vertex, Artios, Prime Oncology, Inbiomotion, Gilead, Corporate-sponsored Research: CJL: AstraZeneca, Merck KGaA, Artios ANJT: Medivation AstraZeneca, Pfizer, Vertex, Artios, Prime Oncology