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Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data.

Jorge SE, Kobayashi SS, Costa DB - Braz. J. Med. Biol. Res. (2014)

Bottom Line: Lung cancer leads cancer-related mortality worldwide.The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models.The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

ABSTRACT
Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC.

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Epidermal growth factor receptor (EGFR) mutations innon-small-cell lung cancer (NSCLC). A, Structure of the kinasedomain of EGFR in complex with erlotinib (based on Protein Data Bank [PDB]accession code 1M17) and location of the most common EGFR mutations.B, Frequency, exon location, and sensitivity to EGFRinhibitors of the most common EGFR mutations. TKIs: tyrosine kinaseinhibitors.
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f02: Epidermal growth factor receptor (EGFR) mutations innon-small-cell lung cancer (NSCLC). A, Structure of the kinasedomain of EGFR in complex with erlotinib (based on Protein Data Bank [PDB]accession code 1M17) and location of the most common EGFR mutations.B, Frequency, exon location, and sensitivity to EGFRinhibitors of the most common EGFR mutations. TKIs: tyrosine kinaseinhibitors.

Mentions: EGFR mutations were initially reported in 2004 and currently define themost prevalent actionable genomically classified subgroup of NSCLC (17-19).EGFR mutations, pertinent to NSCLC, are spatially located within theATP binding site of the kinase (Figure 2A). Themost frequent EGFR mutations (Figure2B) - commonly termed classic or sensitizing activating mutations - arein-frame deletions (around amino acid residues 747 to 750) of exon 19 (45% ofEGFR mutations) and the exon 21 L858R mutation (40% ofEGFR mutations) (20). Thethird most frequent class of EGFR mutations is composed of in-frame insertions withinexon 20 (5-10% of EGFR mutations) of the kinase (21,22). Other recurrentmutations include exon 18 point mutations in position G719 (3% of EGFRmutations), the exon 21 L861Q mutation (2% of EGFR mutations), andin-frame exon 19 insertions (<1% of EGFR mutations) (20,23).EGFR mutations are more frequent in tumors with adenocarcinomahistology, in never-smokers or light smokers, in women with NSCLC, and in patients withEast Asian ethnicities (20). Approximately 15% ofall NSCLCs in patients with European or African ethnicities, 35% of NSCLCs in EastAsians, and 50% of NSCLCs in never-smokers are EGFR mutation positive.The paucity of classic EGFR mutations in tumors with squamous cellcarcinomas of the lung has led to the widespread recommendation of obtaining thegenotype (usually either complete or allele-specific sequencing of key regions of exons18 to 21 of EGFR) only in nonsquamous NSCLCs, except in cases withmixed histologies or with high clinical suspicion (i.e., never-smokers). The College ofAmerican Pathologists, International Association for the Study of Lung Cancer, andAssociation for Molecular Pathology recommend rapid testing for EGFRmutations and ALK rearrangements in all patients with advanced-stageadenocarcinoma (24). The etiology (environmentalor inherited) that underlies the initial genomic insult that either leads to or selectsfor EGFR mutations in lung tissues remains elusive. Interestingly, rareinherited germline EGFR mutations (such as T790M and V843I) can begenomic loci associated with an increased familial clustering of EGFRmutated NSCLC, in which tumors develop when a somatic classic EGFRmutation associates with the inherited allele (5,25).


Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data.

Jorge SE, Kobayashi SS, Costa DB - Braz. J. Med. Biol. Res. (2014)

Epidermal growth factor receptor (EGFR) mutations innon-small-cell lung cancer (NSCLC). A, Structure of the kinasedomain of EGFR in complex with erlotinib (based on Protein Data Bank [PDB]accession code 1M17) and location of the most common EGFR mutations.B, Frequency, exon location, and sensitivity to EGFRinhibitors of the most common EGFR mutations. TKIs: tyrosine kinaseinhibitors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230282&req=5

f02: Epidermal growth factor receptor (EGFR) mutations innon-small-cell lung cancer (NSCLC). A, Structure of the kinasedomain of EGFR in complex with erlotinib (based on Protein Data Bank [PDB]accession code 1M17) and location of the most common EGFR mutations.B, Frequency, exon location, and sensitivity to EGFRinhibitors of the most common EGFR mutations. TKIs: tyrosine kinaseinhibitors.
Mentions: EGFR mutations were initially reported in 2004 and currently define themost prevalent actionable genomically classified subgroup of NSCLC (17-19).EGFR mutations, pertinent to NSCLC, are spatially located within theATP binding site of the kinase (Figure 2A). Themost frequent EGFR mutations (Figure2B) - commonly termed classic or sensitizing activating mutations - arein-frame deletions (around amino acid residues 747 to 750) of exon 19 (45% ofEGFR mutations) and the exon 21 L858R mutation (40% ofEGFR mutations) (20). Thethird most frequent class of EGFR mutations is composed of in-frame insertions withinexon 20 (5-10% of EGFR mutations) of the kinase (21,22). Other recurrentmutations include exon 18 point mutations in position G719 (3% of EGFRmutations), the exon 21 L861Q mutation (2% of EGFR mutations), andin-frame exon 19 insertions (<1% of EGFR mutations) (20,23).EGFR mutations are more frequent in tumors with adenocarcinomahistology, in never-smokers or light smokers, in women with NSCLC, and in patients withEast Asian ethnicities (20). Approximately 15% ofall NSCLCs in patients with European or African ethnicities, 35% of NSCLCs in EastAsians, and 50% of NSCLCs in never-smokers are EGFR mutation positive.The paucity of classic EGFR mutations in tumors with squamous cellcarcinomas of the lung has led to the widespread recommendation of obtaining thegenotype (usually either complete or allele-specific sequencing of key regions of exons18 to 21 of EGFR) only in nonsquamous NSCLCs, except in cases withmixed histologies or with high clinical suspicion (i.e., never-smokers). The College ofAmerican Pathologists, International Association for the Study of Lung Cancer, andAssociation for Molecular Pathology recommend rapid testing for EGFRmutations and ALK rearrangements in all patients with advanced-stageadenocarcinoma (24). The etiology (environmentalor inherited) that underlies the initial genomic insult that either leads to or selectsfor EGFR mutations in lung tissues remains elusive. Interestingly, rareinherited germline EGFR mutations (such as T790M and V843I) can begenomic loci associated with an increased familial clustering of EGFRmutated NSCLC, in which tumors develop when a somatic classic EGFRmutation associates with the inherited allele (5,25).

Bottom Line: Lung cancer leads cancer-related mortality worldwide.The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models.The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

ABSTRACT
Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC.

Show MeSH
Related in: MedlinePlus