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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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Related in: MedlinePlus

Pie chart of the frequency of driver oncogene mutations in lungadenocarcinomas from former/current smokers (left panel) and from never-smokers(right panel). Note the striking difference between the higher frequency ofEGFR, ALK, ROS1, ERBB2, RET, BRAF (V600E), andNTRK1 mutations in never-smokers, and the higher frequency ofKRAS mutations in smokers.
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f01: Pie chart of the frequency of driver oncogene mutations in lungadenocarcinomas from former/current smokers (left panel) and from never-smokers(right panel). Note the striking difference between the higher frequency ofEGFR, ALK, ROS1, ERBB2, RET, BRAF (V600E), andNTRK1 mutations in never-smokers, and the higher frequency ofKRAS mutations in smokers.

Mentions: The last decade has uncovered knowledge on the molecular determinants of lung cancer,and the probing of the NSCLC kinome using next-generation sequencing techniques hasidentified numerous nonoverlapping driver genomic events (i.e., activating mutations orrearrangements) involving targetable kinases, including epidermal growth factor receptor(EGFR), anaplastic lymphoma kinase (ALK), v-Raf murine sarcoma viral oncogene homologB1, V-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2), rearranged duringtransfection, c-ros oncogene 1, and neurotrophic tyrosine kinase receptor type 1, amongothers. Notwithstanding the gaps in knowledge of why NSCLCs develop in never-smokers, itis now well established that never-smoker-related NSCLCs comprise diseases with adistinct biology - compared to smoking-related NSCLCs (where undruggablev-ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations aremore frequent) - marked by an increased incidence of targetable mutations in oncogenes(Figure 1). The near-universal prevalence ofdriver oncogenes in lung adenocarcinomas from never-smokers truly makes these diseasesputative oncogene-driven malignancies, in which the use of kinase inhibitors should beprioritized. The evolving division of NSCLCs into distinct actionable subtypes withmutually exclusive driver oncogenes has helped usher the development of small moleculetyrosine kinase inhibitors (TKIs) that are now either clinically available or in earlyto late stage development as palliative therapies in advanced NSCLC (9-12).


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)

Pie chart of the frequency of driver oncogene mutations in lungadenocarcinomas from former/current smokers (left panel) and from never-smokers(right panel). Note the striking difference between the higher frequency ofEGFR, ALK, ROS1, ERBB2, RET, BRAF (V600E), andNTRK1 mutations in never-smokers, and the higher frequency ofKRAS mutations in smokers.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f01: Pie chart of the frequency of driver oncogene mutations in lungadenocarcinomas from former/current smokers (left panel) and from never-smokers(right panel). Note the striking difference between the higher frequency ofEGFR, ALK, ROS1, ERBB2, RET, BRAF (V600E), andNTRK1 mutations in never-smokers, and the higher frequency ofKRAS mutations in smokers.
Mentions: The last decade has uncovered knowledge on the molecular determinants of lung cancer,and the probing of the NSCLC kinome using next-generation sequencing techniques hasidentified numerous nonoverlapping driver genomic events (i.e., activating mutations orrearrangements) involving targetable kinases, including epidermal growth factor receptor(EGFR), anaplastic lymphoma kinase (ALK), v-Raf murine sarcoma viral oncogene homologB1, V-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2), rearranged duringtransfection, c-ros oncogene 1, and neurotrophic tyrosine kinase receptor type 1, amongothers. Notwithstanding the gaps in knowledge of why NSCLCs develop in never-smokers, itis now well established that never-smoker-related NSCLCs comprise diseases with adistinct biology - compared to smoking-related NSCLCs (where undruggablev-ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations aremore frequent) - marked by an increased incidence of targetable mutations in oncogenes(Figure 1). The near-universal prevalence ofdriver oncogenes in lung adenocarcinomas from never-smokers truly makes these diseasesputative oncogene-driven malignancies, in which the use of kinase inhibitors should beprioritized. The evolving division of NSCLCs into distinct actionable subtypes withmutually exclusive driver oncogenes has helped usher the development of small moleculetyrosine kinase inhibitors (TKIs) that are now either clinically available or in earlyto late stage development as palliative therapies in advanced NSCLC (9-12).

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