title: Comparison of the EGFR resistance mutation profiles generated by EGFR-targeted tyrosine kinase inhibitors and the impact of drug combinations.
abstract: 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 how different classes of targeted therapies impact upon resistance mutations, we performed EGFR (epidermal-growth-factor receptor) 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, whereas 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, whereas mutation of either Gly(796) or Cys(797) 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. The 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 results also indicate that co-expression of ErbB2 (v-erb-b2 erythroblastic leukaemia viral oncogene homologue 2) has an impact upon the EGFR resistance mutations obtained, suggesting that ErbB2 may play an active role in the acquisition of drug-resistant mutations.
authors.affiliation: AstraZeneca, Cancer and Infection Research Area, Macclesfield SK10 4TG, UK.
authors.forename: Egle
authors.initials: E
authors.lastname: Avizienyte
authors.forename: Richard A
authors.initials: RA
authors.lastname: Ward
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Garner
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D015151:Immunoblotting; D047468:Immunoprecipitation; D007377:Interleukin-3 / Q000378:metabolism; D000077341:Lapatinib; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D004338:Drug Combinations; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D007377:Interleukin-3; D000077341:Lapatinib; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C420268:Canertinib