Comparison of the EGFR resistance mutation profiles generated by EGFR targeted tyrosine kinase inhibitors and the impact of drug combinations

Egle Avizienyte , Richard A Ward , Andrew P Garner (1)

1 AstraZeneca

Recent clinical data indicates that the emergence of mutant drug-resistant kinase alleles may be particularly relevant for targeted kinase inhibitors. In order to explore the how different classes of targeted therapies impact upon resistance mutations we performed EGFR resistance mutation screens with erlotinib, lapatinib and CI-1033. Distinct mutation spectra were generated with each inhibitor and were reflective of their respective mechanisms of action. Lapatinib yielded the widest variety of mutations, whilst mutational variability was lower in the erlotinib and CI-1033 screens. Lapatinib was uniquely sensitive to mutations of residues located deep within the selectivity pocket, whilst mutation of either G796 or C797 resulted in a dramatic loss of CI-1033 potency. The clinically observed T790M mutation was common to all inhibitors but occurred with varying frequencies. Importantly, the presence of C797S with T790M in the same EGFR allele conferred complete resistance to erlotinib, lapatinib and CI-1033. Combination of erlotinib and CI-1033 effectively reduced the number of drug resistant clones suggesting a possible clinical strategy to overcome drug resistance. Interestingly, our data also indicates that co-expression of ErbB2 has an impact upon the EGFR resistance mutations obtained suggesting that ErbB2 may play an active role in the acquisition of drug resistant mutations.

Mots clés: Life Sciences

Egle Avizienyte, Richard A Ward, Andrew P Garner. Comparison of the EGFR resistance mutation profiles generated by EGFR targeted tyrosine kinase inhibitors and the impact of drug combinations. Biochemical Journal, 2008, 415 (2), pp.197-206. ⟨10.1042/BJ20080728⟩. ⟨hal-00479008⟩