Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA

Playing Hide and Seek Targeted cancer therapies have shown promising results in patients, but few of these drugs provide long-term benefits because tumor cells rapidly develop drug resistance. Nathanson et al. (p. 72 , published online 5 December) show that glioblastoma cells can become resistant to erlotinib, an epidermal growth factor receptor (EGFR)–targeted drug, by eliminating extrachromosomal copies of the mutant EGFR gene. After a period of drug withdrawal, the mutant EGFR gene reappears on extrachromosomal DNA and the tumor cells become resensitized. The discovery that cancer cells can evade drug therapy by this “hide and seek” mechanism may help to optimize the dosing schedule of erlotinib in glioblastoma patients.