Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma Journal Article
| Authors: | Bean, J.; Riely, G. J.; Balak, M.; Marks, J. L.; Ladanyi, M.; Miller, V. A.; Pao, W. |
| Article Title: | Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma |
| Abstract: | Purpose: Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are associated with sensitivity of lung adenocarcinomas to the EGFR tyrosine kinase inhibitors, gefitinib and erlotinib. Acquired drug resistance is frequently associated with a secondary somatic mutation that leads to the substitution of methionine for threonine at position 790 (T790M). We aimed to identify additional second-site alterations associated with acquired resistance. Experimental Design: Tumor samples were obtained from 48 patients with acquired resistance. Tumor cell DNA was analyzed for EGFR kinase domain mutations. Molecular analyses were then done to characterize the biological properties of a novel mutant EGFR allele. Results: A previously unreported mutation in exon 21 of EGFR, which leads to substitution of alanine for threonine at position 854 (T854A), was identified in one patient with a drug-sensitive EGFR L858R-mutant lung adenocarcinoma after long-term treatment with tyrosine kinase inhibitors. The T854A mutation was not detected in a pretreatment tumor sample. The crystal structure analyses of EGFR suggest that the T854 side chain is within contact distance of gefitinib and erlotinib. Surrogate kinase assays show that the EGFR T854A mutation abrogates the inhibition of tyrosine phosphorylation by erlotinib. Such resistance seems to be overcome by a new irreversible dual EGFR/HER2 inhibitor, BIBW2992. Conclusions: The T854A mutation is the second reported second-site acquired resistance mutation that is within contact distance of gefitinib and erlotinib. These data suggest that acquired resistance to ATP-mimetic EGFR kinase inhibitors may often be associated with amino acid substitutions that alter drug contact residues in the EGFR ATP-binding pocket. ©2008 American Association for Cancer Research. |
| Keywords: | controlled study; human tissue; protein phosphorylation; aged; unclassified drug; gene mutation; human cell; major clinical study; exon; genetics; mutation; case report; erlotinib; drug withdrawal; antineoplastic agents; temozolomide; molecular genetics; antineoplastic agent; polymerase chain reaction; sensitivity analysis; adenocarcinoma; allele; imatinib; amino acid substitution; protein kinase inhibitor; thrombocytopenia; lung neoplasms; epidermal growth factor receptor; receptor, epidermal growth factor; drug structure; drug resistance; drug resistance, neoplasm; cell line, tumor; protein kinase inhibitors; lung tumor; chemistry; lung adenocarcinoma; amino acid sequence; molecular sequence data; drug mechanism; sequence alignment; nucleotide sequence; tumor cell line; gefitinib; tumor cell; immunoblotting; base sequence; crystal structure; threonine; alanine; molecular biology; ic 50; quinazolines; protein structure, quaternary; lapatinib; quinazoline derivative; enzyme assay; epidermal growth factor receptor kinase; epidermal growth factor receptor kinase inhibitor; bibw 2992; cell dna; restriction fragment length polymorphism; polymorphism, restriction fragment length; protein quaternary structure |
| Journal Title: | Clinical Cancer Research |
| Volume: | 14 |
| Issue: | 22 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2008-11-15 |
| Start Page: | 7519 |
| End Page: | 7525 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-08-0151 |
| PUBMED: | 19010870 |
| PROVIDER: | scopus |
| PMCID: | PMC2596620 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 50" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Molecular Sequence Numbers: GENBANK: NP_000133, NP_000213, NP_000236, NP_002010, NP_002011, NP_002218, NP_002521, NP_002600, NP_002812, NP_002935, NP_003322, NP_004110, NP_004324, NP_004374, NP_004422, NP_004430, NP_004432, NP_004434, NP_004693, NP_005003, NP_005148, NP_005224, NP_006197, NP_006334, NP_056934, NP_065387, NP_065681, NP_075599;" - "Source: Scopus" |
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