title: Mutation of threonine 766 in the epidermal growth factor receptor reveals a hotspot for resistance formation against selective tyrosine kinase inhibitors.
abstract: Small molecule inhibitors of protein tyrosine kinases such as STI571 represent a major new class of therapeutics for target-selective treatment of human cancer. Clinical resistance formation to the BCR-ABL inhibitor STI571 has been observed in patients with advanced chronic myeloid leukemia and was frequently caused by a C to T single nucleotide change in the Abl kinase domain, which substituted Thr-315 with isoleucine and rendered BCR-ABL resistant to STI571 inhibition. The corresponding mutation in the epidermal growth factor receptor (EGFR) tyrosine kinase replaced Thr-766 of the EGFR by methionine and dramatically reduced the sensitivity of EGFR to inhibition by selective 4-anilinoquinazoline inhibitors such as PD153035. Inhibitor-resistant EGFR exhibited the same signaling capacity as wild-type receptor in vivo and provides a useful tool for analyzing EGFR-mediated signal transduction. Our data identify Thr-766 of the EGFR as a structural determinant that bears the potential to become a relevant feature in resistance formation during cancer therapy with EGFR-specific 4-anilinoquinazoline inhibitors.
authors.affiliation: Axxima Pharmaceuticals AG, Max-Lebsche-Platz 32, 81377 München, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Blencke
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
authors.forename: Henrik
authors.initials: H
authors.lastname: Daub
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D002460:Cell Line; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D020935:MAP Kinase Signaling System; D010879:Piperazines / Q000494:pharmacology; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D013912:Threonine / Q000235:genetics; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D011799:Quinazolines; D013912:Threonine; D000068877:Imatinib Mesylate; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline