Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.

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Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA

Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.

N Engl J Med. 2004 May 20;350(21):2129-39. Epub 2004 Apr 29.

PubMed ID

15118073 [ View in PubMed

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Abstract

BACKGROUND: Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. METHODS: We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. RESULTS: Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. CONCLUSIONS: A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.

DrugBank Data that Cites this Article

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Gefitinib	Epidermal growth factor receptor Gene symbol: EGFR UniProt: P00533	L858R	(G;G) / (G;T)	T > G (rs121434568)	Effect Directly Studied	The presence of this polymorphism in EGFR is associated with a higher response rate to gefitinib.	Details
Gefitinib	Epidermal growth factor receptor Gene symbol: EGFR UniProt: P00533	G719A/C	(T;T) / (G;T) / (A;A) / (A;G) / (C;C) / (C;G)	G > A or C or T (rs28929495)	Effect Directly Studied	The presence of this polymorphism in EGFR is associated with a higher response rate to gefitinib.	Details
Gefitinib	Epidermal growth factor receptor Gene symbol: EGFR UniProt: P00533	L861Q	(A;A) / (A;T) / (G;G) / (G;T)	T > A or G (rs121913444)	Effect Directly Studied	The presence of this polymorphism in EGFR is associated with a higher response rate to gefitinib.	Details
Erlotinib	Epidermal growth factor receptor Gene symbol: EGFR UniProt: P00533	G719A/C	(T;T) / (G;T) / (A;A) / (A;G) / (C;C) / (C;G)	G > A or C or T (rs28929495)	Effect Directly Studied	The presence of this polymorphism in EGFR is associated with a higher response rate to erlotinib.	Details
Erlotinib	Epidermal growth factor receptor Gene symbol: EGFR UniProt: P00533	L861Q	(A;A) / (A;T) / (G;G) / (G;T)	T > A or G (rs121913444)	Effect Directly Studied	The presence of this polymorphism in EGFR is associated with a higher response rate to erlotinib.	Details
Erlotinib	Epidermal growth factor receptor Gene symbol: EGFR UniProt: P00533	L858R	(G;G) / (G;T)	T > G (rs121434568)	Effect Directly Studied	The presence of this polymorphism in EGFR is associated with a higher response rate to erlotinib.	Details
Afatinib	Epidermal growth factor receptor Gene symbol: EGFR UniProt: P00533	L861Q	(A;A) / (A;T) / (G;G) / (G;T)	T > A or G (rs121913444)	Effect Directly Studied	The presence of this polymorphism in EGFR is associated with a higher response rate to afatinib.	Details
Afatinib	Epidermal growth factor receptor Gene symbol: EGFR UniProt: P00533	L858R	(G;G) / (G;T)	T > G (rs121434568)	Effect Directly Studied	The presence of this polymorphism in EGFR is associated with a higher response rate to afatinib.	Details
Afatinib	Epidermal growth factor receptor Gene symbol: EGFR UniProt: P00533	G719A/C	(T;T) / (G;T) / (A;A) / (A;G) / (C;C) / (C;G)	G > A or C or T (rs28929495)	Effect Directly Studied	The presence of this polymorphism in EGFR is associated with a higher response rate to afatinib.	Details