EGFR resistance mutations

These observations are consistent with clinical observation. The T790M has been detected in 50% of patients resistant to gefitinib or erlotinib.75,76 This resistance, as measured by circulating tumor cells harboring T790M, has been shown to increase over time,77 and to be present in untreated patients.78 In the latter study, detection of T790M prior to treatment reduced progression free survival times from 16.5 months to 7.7 months.77 

A crystal structure of the mutant T790M kinase is available that shows the new gatekeeper methionine able to move to accommodate a bound inhibitor. This is consistent with the observed binding of inhibitors to mutant and double mutant kinases containing this mutation.74 

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Table 5.3 Design strategies to overcome resistance mutations in EGFR and Her2.

Pao, W., Miller, V. A., PoUti, K. A., et al. (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2, e73. 

Wang SE, Narasanna A, Perez-Torres M et al. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 2006 10 25-38. 

The development of other somatic mutations in survival signaUng with the tumor cell, such as loss of PTEN (phosphatase and tensin homologue deleted in chromosome 10) function, which may be selected for in tumor ceUs undergoing EGFR inhibitor therapy, wiU lead to the development of tumor ceUs that are more resistant in general to the inhibitors of growth factor receptors. 

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