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EGFR TKI acquired resistance

Wednesday 5 June 2013

Somatic mutations in genes encoding kinases are associated with increased sensitivity of some solid tumors to kinase inhibitors, but patients with metastatic cancer eventually develop disease progression.

A common method used to model acquired resistance involves culturing parental drug-sensitive cells with increasing concentrations of drug until cells emerge that are resistant.

In EGFR mutant lung cancer, this modeling has reliably identified clinically relevant EGFR tyrosine kinase inhibitor (TKI) resistance mechanisms such as the second-site mutation, EGFR T790M, amplification of the gene encoding an alternative kinase, MET, and epithelial-mesenchymal transition (EMT).

The full spectrum of DNA changes associated with EGFR TKI acquired resistance remains unknown.

Some results demonstrate a framework for studying the evolution of drug-related genetic variants over time and provide the first genome-wide spectrum of mutations associated with the development of cellular drug resistance in an oncogene-addicted cancer.

Collectively, the data suggest that CNV changes may play a larger role than previously appreciated in the acquisition of drug resistance and highlight that resistance may be heterogeneous in the context of different tumor cell backgrounds.

References

- Detection of EGFR T790M mutation in plasma DNA from patients refractory to EGFR tyrosine kinase inhibitor. Sakai K, Horiike A, Irwin DL, Kudo K, Fujita Y, Tanimoto A, Sakatani T, Saito R, Kaburaki K, Yanagitani N, Ohyanagi F, Nishio M, Nishio K. Cancer Sci. 2013 May 31. doi : 10.1111/cas.12211 PMID: 23721103

- Next-generation sequencing of paired tyrosine kinase inhibitor-sensitive and -resistant EGFR mutant lung cancer cell lines identifies spectrum of DNA changes associated with drug resistance. Jia P, Jin H, Meador CB, Xia J, Ohashi K, Liu L, Pirazzoli V, Dahlman KB, Politi K, Michor F, Zhao Z, Pao W. Genome Res. 2013 Jun 3. PMID: 23733853