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Second generation tyrosine kinase inhibitors for the treatment of metastatic non-small-cell lung cancer.

Stasi I, Cappuzzo F - Transl Respir Med (2014)

Bottom Line: However, after an initial response, all patients inevitably progress and several mechanisms including a secondary mutation in exon 20 of the EGFR gene (T790M) or MET or HER2 amplifications are responsible for acquired resistance (AR).In clinical practice few options are available for patients with AR, and several new agents or strategies are currently under investigation, including second generation TKIs.Aim of the present review is to present available data on new EGFR-TKIs and to discuss how these agents could overcome AR to erlotinib or gefitinib.

View Article: PubMed Central - PubMed

Affiliation: Medical Oncology Department, IstitutoToscanoTumori, OspedaleCivile, Livorno, Italy.

ABSTRACT

Backgruond: Since their first description, activating epidermal growth factor receptor (EGFR) mutations identify a distinct clinical entity of patients with non-small-cell lung cancer (NSCLC).

Findings: New targeted therapies for molecularly selected NSCLC are changing the natural history of the disease, with results superior to standard chemotherapy as demonstrated in large phase III studies with first generation EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. However, after an initial response, all patients inevitably progress and several mechanisms including a secondary mutation in exon 20 of the EGFR gene (T790M) or MET or HER2 amplifications are responsible for acquired resistance (AR). In clinical practice few options are available for patients with AR, and several new agents or strategies are currently under investigation, including second generation TKIs.

Conclusions: Aim of the present review is to present available data on new EGFR-TKIs and to discuss how these agents could overcome AR to erlotinib or gefitinib.

No MeSH data available.


Related in: MedlinePlus

Epidermal Growth Factor Receptor Family and intracellular pathway (adapted fromhttp://nature.com).
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Fig2: Epidermal Growth Factor Receptor Family and intracellular pathway (adapted fromhttp://nature.com).

Mentions: EGFR mutations identify a distinct subgroup of NSCLC characterized by oncogene addiction, for which cell’s growth and survival signals are dependent upon EGFR activation. In this scenario, cells would develop resistance mechanisms that reactivate EGFR despite the presence of an inhibitor, as the acquired T790M second site mutation in the exon 20 of EGFR gene. The T790M missense mutation could be classified as the gatekeeper mutation, occurring within the ATP-binding site and interfering with the first-generation TKI’s binding by steric hindrance, causing a bulky methionine side chain in the receptor kinase domain [19]. In vitro studies showed that exposing EGFR-mutant lung cancer cell lines to a mutagen and culturing them in the presence of an EGFR-TKI, the resistant clones with the T790M mutation maintained a persistent phosphorylation [20]. Given this role of persistent EGFR signaling, many trials evaluated the intensification of EGFR inhibition through the use of drug molecules with additional activity against other receptors in the EGFR family, as the second-generation neratinib, dacomitinib and afatinib [21]. These inhibitors are mainly different from erlotinib and gefitinib for two features: each forms a covalent and irreversible attachment to the EGFR kinase domain, and each also inhibits other members of the ERBB family (Figure 2).Figure 2


Second generation tyrosine kinase inhibitors for the treatment of metastatic non-small-cell lung cancer.

Stasi I, Cappuzzo F - Transl Respir Med (2014)

Epidermal Growth Factor Receptor Family and intracellular pathway (adapted fromhttp://nature.com).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215821&req=5

Fig2: Epidermal Growth Factor Receptor Family and intracellular pathway (adapted fromhttp://nature.com).
Mentions: EGFR mutations identify a distinct subgroup of NSCLC characterized by oncogene addiction, for which cell’s growth and survival signals are dependent upon EGFR activation. In this scenario, cells would develop resistance mechanisms that reactivate EGFR despite the presence of an inhibitor, as the acquired T790M second site mutation in the exon 20 of EGFR gene. The T790M missense mutation could be classified as the gatekeeper mutation, occurring within the ATP-binding site and interfering with the first-generation TKI’s binding by steric hindrance, causing a bulky methionine side chain in the receptor kinase domain [19]. In vitro studies showed that exposing EGFR-mutant lung cancer cell lines to a mutagen and culturing them in the presence of an EGFR-TKI, the resistant clones with the T790M mutation maintained a persistent phosphorylation [20]. Given this role of persistent EGFR signaling, many trials evaluated the intensification of EGFR inhibition through the use of drug molecules with additional activity against other receptors in the EGFR family, as the second-generation neratinib, dacomitinib and afatinib [21]. These inhibitors are mainly different from erlotinib and gefitinib for two features: each forms a covalent and irreversible attachment to the EGFR kinase domain, and each also inhibits other members of the ERBB family (Figure 2).Figure 2

Bottom Line: However, after an initial response, all patients inevitably progress and several mechanisms including a secondary mutation in exon 20 of the EGFR gene (T790M) or MET or HER2 amplifications are responsible for acquired resistance (AR).In clinical practice few options are available for patients with AR, and several new agents or strategies are currently under investigation, including second generation TKIs.Aim of the present review is to present available data on new EGFR-TKIs and to discuss how these agents could overcome AR to erlotinib or gefitinib.

View Article: PubMed Central - PubMed

Affiliation: Medical Oncology Department, IstitutoToscanoTumori, OspedaleCivile, Livorno, Italy.

ABSTRACT

Backgruond: Since their first description, activating epidermal growth factor receptor (EGFR) mutations identify a distinct clinical entity of patients with non-small-cell lung cancer (NSCLC).

Findings: New targeted therapies for molecularly selected NSCLC are changing the natural history of the disease, with results superior to standard chemotherapy as demonstrated in large phase III studies with first generation EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. However, after an initial response, all patients inevitably progress and several mechanisms including a secondary mutation in exon 20 of the EGFR gene (T790M) or MET or HER2 amplifications are responsible for acquired resistance (AR). In clinical practice few options are available for patients with AR, and several new agents or strategies are currently under investigation, including second generation TKIs.

Conclusions: Aim of the present review is to present available data on new EGFR-TKIs and to discuss how these agents could overcome AR to erlotinib or gefitinib.

No MeSH data available.


Related in: MedlinePlus