Researchers from Singapore’s A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB) report that they have identified why certain lung cancer cells become highly resistant to treatment after developing mutations in the EGFR (epidermal growth factor receptor) gene. In a study “A genome-wide genetic screen reveals the P2Y2-integrin axis as a stabilizer of EGFR mutants in non–small cell lung cancer (NSCLC)” published in Science Advances, the team revealed a previously unknown survival mechanism and demonstrated that disrupting it can shrink tumors in laboratory models. Many lung cancer cases are driven by mutations in the EGFR gene. In Southeast Asia, these mutations appear in up to 40–60% of adenocarcinoma. While targeted drugs initially work well against these cancers, nearly all patients eventually stop responding. Scientists have long puzzled over why the faulty proteins produced by mutant EGFR are so stable, while normal proteins are recycled via degradation. These mutant versions persist far longer than they should. Genome-wide screen The investigators screened more than 21,000 genes to identify what protects these mutant proteins from being broken down. They discovered that cancer cells flood their surroundings with ATP, a molecule normally used for energy. This excess ATP switches on the P2Y2, which then recruits a partner protein, integrin β1, to form a protective barrier around the mutant EGFR. The barrier stops the faulty protein from reaching the cell’s recycling center. Instead, the protected protein remains active and continues to drive cancer growth. The team confirmed these findings in human cancers by examining tissue…
