Targeted cancer therapies are designed to target the specific genes, proteins, or environments contributing to tumor cell growth or survival. After a period of prolonged treatment with these therapies, however, tumor cells may develop resistance. Although the mechanisms behind cancer drug resistance are poorly understood, potential causes include: target alteration, drug degradation, apoptosis escape, and epigenetic alterations. Resistance is well-recognised and poses a serious problem in cancer management.
To overcome this problem, a synthetic lethal partner can be identified. Genome-wide LOF screens using CRISPR-Cas9 can be used to screen for synthetic lethal partners. For this, a wild-type cell line and a tumor cell line containing the resistance-causing mutation are transduced with a CRISPR sgRNA library. The two cell lines are cultivated, and any under-represented or dead cells are analyzed to identify potential synthetic lethal partner genes. A recent study by Hinze et al. (2019) used this method to identify a synthetic lethal interaction between the chemotherapy drug asparaginase and two genes in the Wnt signalling pathway NKD2 and LGR6.