Chromosomal Instability and 17p Loss Sensitize Cancer Cells to NDE1 Depletion

PROJECT SUMMARY Chromosomal Instability (CIN) and loss of the short arm of chromosome 17 (17p) are interrelated and relatively common characteristics of many advanced, metastatic cancers. Though these genetic alterations are likely to contribute to synthetic lethalities, the genetic dependencies resulting from CIN and 17p loss have not been extensively identified or explored. A whole-genome CRISPR/Cas9 screen performed in our lab comparing primary and metastatic-derivative cell lines revealed that metastatic tumors, which possess higher rates of chromosomal instability, are more sensitive to inhibition of mitotic regulators associated with chromosome segregation. Knockout of one such regulator, NDE1, selectively inhibited the growth of metastatic, CIN-high cell lines in vitro, and in vivo. Interestingly, dependence on NDE1 is highly correlated with loss of 17p across cell lines in the DepMap database, indicating that both CIN and 17p loss may contribute to NDE1 sensitivity. We hypothesize that inhibiting NDE1 may be an effective way to target cancers harboring 17p loss and increased CIN through a unique, dual action mechanism involving the buildup of errors in faithful chromosome segregation, and synthetic lethality with an NDE1 paralog and binding partner, both of which are located on 17p. To test this central hypothesis, I propose defining the relationship between NDE1 dependence, 17p loss, and chromosomal instability, characterizing the role of NDE1 in proper chromosome segregation, and assessing the therapeutic potential of targeting NDE1 in the context of CIN and 17p loss.