Novel D761Y and Common Secondary T790M Mutations in Epidermal Growth Factor Receptor–Mutant Lung Adenocarcinomas with Acquired Resistance to Kinase Inhibitors

• Published in: Clinical cancer research 2006-11, Vol.12 (21), p.6494-6501
• Main Authors: BALAK, Marissa N, YIXUAN GONG, LADANYI, Marc, MILLER, Vincent A, PAOL, William, RIELY, Gregory J, SOMWAR, Romel, LI, Allan R, ZAKOWSKI, Maureen F, CHIANG, Anne, GUANGLI YANG, OUERFELLI, Ouathek, KRIS, Mark G
• Format: Article
• Language: English
• Subjects: acquired resistance; Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Amino Acid Sequence; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Biological and medical sciences; DNA Mutational Analysis; Drug Resistance, Neoplasm - genetics; epidermal growth factor receptor; Erlotinib Hydrochloride; Gene Dosage; Humans; In Situ Hybridization; lung adenocarcinoma; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Medical sciences; Molecular Sequence Data; Mutation; Neoplasm Metastasis - genetics; Pharmacology. Drug treatments; Pneumology; Protein Kinase Inhibitors - therapeutic use; Protein Structure, Tertiary; Quinazolines - therapeutic use; Receptor, Epidermal Growth Factor - chemistry; Receptor, Epidermal Growth Factor - drug effects; Receptor, Epidermal Growth Factor - genetics; Reverse Transcriptase Polymerase Chain Reaction; Tumors of the respiratory system and mediastinum; tyrosine kinase inhibitor
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-1570

Purpose: In patients whose lung adenocarcinomas harbor epidermal growth factor receptor (EGFR) tyrosine kinase domain mutations, acquired resistance to the tyrosine kinase inhibitors (TKI) gefitinib (Iressa) and erlotinib (Tarceva) has been associated with a second-site EGFR mutation, which leads to substitution of methionine for threonine at position 790 (T790M). We aimed to elucidate the frequency and nature of secondary EGFR mutations in patients with acquired resistance to TKI monotherapy. Experimental Design: Tumor cells from patients with acquired resistance were examined for secondary EGFR kinase domain mutations by molecular analyses. Results: Eight of 16 patients (50% observed rate; 95% confidence interval, 25-75%) had tumor cells with second-site EGFR mutations. Seven mutations were T790M and one was a novel D761Y mutation found in a brain metastasis. When combined with a drug-sensitive L858R mutation, the D761Y mutation modestly reduced the sensitivity of mutant EGFR to TKIs in both surrogate kinase and cell viability assays. In an autopsy case, the T790M mutation was found in multiple visceral metastases but not in a brain lesion. Conclusions: The T790M mutation is common in patients with acquired resistance. The limited spectrum of TKI-resistant mutations in EGFR , which binds to erlotinib in the active conformation, contrasts with a wider range of second-site mutations seen with acquired resistance to imatinib, which binds to ABL and KIT, respectively, in closed conformations. Collectively, our data suggest that the type and nature of kinase inhibitor resistance mutations may be influenced by both anatomic site and mode of binding to the kinase target.