Limits...
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.

Show MeSH

Related in: MedlinePlus

A, Mechanism of activation of the JAK/STAT, MAPK/ERK and PI3K/AKTpathways by epidermal growth factor receptor (EGFR) mutations and their inhibitionby EGFR tyrosine kinase inhibitors (TKIs). B, Mechanisms ofacquired resistance to EGFR TKIs in EGFR mutated non-small-celllung cancer (NSCLC) with emphasis on the EGFR-T790M resistant mutation andoncogene bypass tracks that re-activate downstream signaling cascades.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4230282&req=5

f03: A, Mechanism of activation of the JAK/STAT, MAPK/ERK and PI3K/AKTpathways by epidermal growth factor receptor (EGFR) mutations and their inhibitionby EGFR tyrosine kinase inhibitors (TKIs). B, Mechanisms ofacquired resistance to EGFR TKIs in EGFR mutated non-small-celllung cancer (NSCLC) with emphasis on the EGFR-T790M resistant mutation andoncogene bypass tracks that re-activate downstream signaling cascades.

Mentions: EGFR mutations, by favoring the active kinase state, are oncogenic inNSCLC cell lines, mouse models, and human tumors. They do this by inducing EGFR-mediatedantiapoptotic and prosurvival proteins via downstream targets of the mitogen-activatedprotein kinase/extracellular-signal-regulated kinase, janus kinase/signal transducer andactivator of transcription, and phosphatidylinositol-3-kinase/protein kinase B cascades(14). These signaling networks make cells withEGFR mutations dependent on this ErbB member for their survival(Figure 3A). EGFR mutant inhibition leads toupregulation and activation of proapoptotic molecules that initiate the intrinsicmitochondrial apoptotic pathway by affecting the balance of pro- vsantiapoptotic BCL-2 family members. The most well-described apoptotic signal induced byEGFR inhibition is that of the BH3 domain-only molecule BIM (Figure 3A), which in the mitochondria binds to antiapoptotic BCL-2members and antagonizes their antiapoptotic activity (29). Therefore, the apoptotic response induced by EGFR TKIs defines anoncogene-addicted model.


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)

A, Mechanism of activation of the JAK/STAT, MAPK/ERK and PI3K/AKTpathways by epidermal growth factor receptor (EGFR) mutations and their inhibitionby EGFR tyrosine kinase inhibitors (TKIs). B, Mechanisms ofacquired resistance to EGFR TKIs in EGFR mutated non-small-celllung cancer (NSCLC) with emphasis on the EGFR-T790M resistant mutation andoncogene bypass tracks that re-activate downstream signaling cascades.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f03: A, Mechanism of activation of the JAK/STAT, MAPK/ERK and PI3K/AKTpathways by epidermal growth factor receptor (EGFR) mutations and their inhibitionby EGFR tyrosine kinase inhibitors (TKIs). B, Mechanisms ofacquired resistance to EGFR TKIs in EGFR mutated non-small-celllung cancer (NSCLC) with emphasis on the EGFR-T790M resistant mutation andoncogene bypass tracks that re-activate downstream signaling cascades.
Mentions: EGFR mutations, by favoring the active kinase state, are oncogenic inNSCLC cell lines, mouse models, and human tumors. They do this by inducing EGFR-mediatedantiapoptotic and prosurvival proteins via downstream targets of the mitogen-activatedprotein kinase/extracellular-signal-regulated kinase, janus kinase/signal transducer andactivator of transcription, and phosphatidylinositol-3-kinase/protein kinase B cascades(14). These signaling networks make cells withEGFR mutations dependent on this ErbB member for their survival(Figure 3A). EGFR mutant inhibition leads toupregulation and activation of proapoptotic molecules that initiate the intrinsicmitochondrial apoptotic pathway by affecting the balance of pro- vsantiapoptotic BCL-2 family members. The most well-described apoptotic signal induced byEGFR inhibition is that of the BH3 domain-only molecule BIM (Figure 3A), which in the mitochondria binds to antiapoptotic BCL-2members and antagonizes their antiapoptotic activity (29). Therefore, the apoptotic response induced by EGFR TKIs defines anoncogene-addicted model.

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