Chromosomal instability and chromosome 17p loss drive convergent <i>NDE1</i> synthetic lethality in metastatic cancer cells

Recent studies have identified recurrent features of metastatic cancer cells such as their increased chromosomal instability (CIN) and frequent loss of the short arm of chromosome 17 (Chr17p). However, it remains unclear whether these features induce synthetic lethal vulnerabilities that can be used to specifically target metastatic disease. Using whole-genome CRISPR/Cas9 loss-of-function screens performed in matched primary and CIN-high brain-metastatic tumor models, we discovered that brain-metastatic cells exhibit increased sensitivity to the loss of diverse regulators of chromosome segregation. Knockout of one such regulator, <i>NDE1,</i> selectively inhibited the growth of brain-metastatic models <i>in vitro</i> and <i>in vivo</i> , an effect driven by the loss of STAG2 and consequent induction of CIN. Surprisingly, dependence on <i>NDE1</i> was also highly correlated with loss of Chr17p across hundreds of cancer cell lines in DepMap, the result of losing the <i>NDE1</i> paralog <i>NDEL1</i> , which resides at this locus. CIN and Chr17p loss are thus independently sufficient to drive <i>NDE1</i> dependence in brain-metastatic cells, and the presence of both features increases <i>NDE1</i> dependence additively. These findings demonstrate that metastasis evolution endows cancer cells with specific vulnerabilities, including one that is driven by two recurrently altered molecular features of metastatic disease.