Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA
By D. Nathanson, B. Gini, J. Mottahedeh, Koppany Visnyei, Tomoyuki Koga, G. Gomez, Ascia Eskin, Kiwook Hwang, Jun Wang, Kenta Masui and 15 more. Science, 2013
628 citations recorded by the source corpus.
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. Tumor cells become resistant to targeted therapies by eliminating the gene encoding the drug target from extrachromosomal DNA. Intratumoral heterogeneity contributes to cancer drug resistance, but the underlying mechanisms are not understood. Single-cell analyses of patient-derived models and clinical samples from glioblastoma patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate that tumor cells reversibly up-regulate or suppress mutant EGFR expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth. Resistance to EGFR TKIs is shown to occur by elimination of mutant EGFR from extrachromosomal DNA. After drug withdrawal, reemergence of clonal EGFR mutations on extrachromosomal DNA follows. These results indicate a highly specific, dynamic, and adaptive route by which cancers can evade therapies that target oncogenes maintained on extrachromosomal DNA.
Subfields: Cancer Research, Genetics, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/36975e367060838d48b1b4ae95074bdaadb62d29
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Citations in the corpus
- Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “…changes mediated by extrachromosomal DNA, which avoids fitness cost of large-scale chromosomal changes, while providing a highly dynamic focused diversification mechanism, enabling populations of tumor cells to quickly find optimum under therapy-imposed selection pressures (Nathanson et al., 2014).”