In virtually all non-small-cell lung cancer (NSCLC) patients who exhibit dramatic responses to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), gefitinib (Iressa), or erlotinib (Tarceva), the disease eventually progresses. Recently, we and others have shown that 4 of 7 patients with such “acquired resistance” contain tumors with a second mutation in the EGFR kinase domain after progression, in addition to primary drug-sensitive EGFR mutations. From crystal structure analyses, the resulting amino acid change (T790M) is predicted to block binding of drug to the ATP pocket via steric clash resulting from introduction of the bulky methionine residue. Whether NSCLC patients who develop T790M-mediated resistance to gefitinib or erlotinib can be treated with other targeted agents is unknown. Furthermore, mechanisms underlying secondary resistance in the remainder of cases remain to be elucidated.
The overall goal of this project is to identify clinically relevant mechanisms of acquired resistance to gefitinib and erlotinib and to begin testing strategies to overcome acquired resistance. Specifically, we aim to: 1) determine the changes in EGFR sequence or copy number that occur on treatment failure in more patients (up to 80 individuals) initially sensitive to gefitinib or erlotinib, and establish how newly “acquired” mutations affect biochemical properties of EGFR, such as kinase activity and sensitivity to EGFR TKIs; 2) characterize transgenic animals carrying tetracycline-inducible transgenes that encode the common T790M resistance mutation by itself and in the context of a drug-sensitive EGFR mutation (L858R), comparing them to mice that express the drug-sensitive EGFR mutation (L858R) alone; and 3) identify targeted agents and strategies to overcome acquired resistance to gefitinib or erlotinib. Ultimately, we hope to determine the most effective way of integrating new strategies into the clinic to both treat progressive disease and suppress the development of acquired resistance.