Genome-wide CRISPR screening reveals genetic modifiers of mutant EGFR dependence in human NSCLC

Cancer is caused by cells growing and dividing uncontrollably as a result of mutations in certain genes. Many human lung cancers have a mutation in the gene that makes the protein EGFR. In healthy cells, EGFR allows a cell to respond to chemical signals that encourage healthy growth. In cancer, the altered EGFR is always on, which allows the cell to rapidly grow without any control, resulting in cancer. One approach to treating these cancers is with drugs that block the activity of mutant EGFR. Although these drugs have been very successful, they do not always succeed in completely treating the cancer. This is because over time the cancer cells can become resistant to the drug and start forming new tumors. One way that this can happen is if random mutations lead to changes in other proteins that make the drug less effective or stop it from accessing the EGFR proteins. However, it is unclear how other proteins in cancer cells affect the response to these EGFR inhibiting drugs. Now, Zeng et al. have used gene editing to systematically remove every protein from human lung cancer cells grown in the laboratory to see how this affects resistance to EGFR inhibitor treatment. This revealed that a number of different proteins could change how cancer cells responded to the drug. For instance, cells lacking the protein RIC8A were more sensitive to EGFR inhibitors and less likely to develop resistance. This is because loss of RIC8A turns down a key cell survival pathway in cancer cells. Whereas, cancer cells lacking the ARIH2 protein were able to produce more proteins that are needed for cancer cell growth, which resulted in them having increased resistance to EGFR inhibitors. The proteins identified in this study could be used to develop new drugs that improve the effectiveness of EGFR inhibitors. Understanding how cancer cells respond to EGFR inhibitor treatment could help determine how likely a patient is to develop resistance to these drugs.