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Personalized targeted therapy for lung cancer.

Wu K, House L, Liu W, Cho WC - Int J Mol Sci (2012)

Bottom Line: Personalized medicine refers to the use of markers to predict which patient will most likely benefit from a treatment.In lung cancer, the well-developed epidermal growth factor receptor (EGFR) and the newly emerging EML4-anaplastic lymphoma kinase (ALK) are important therapeutic targets.Nevertheless, it is foreseeable that the sequencing and systems strategies may offer a solution for those patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA; E-Mails: kwu@bsd.uchicago.edu (K.W.); lhouse@medicine.bsd.uchicago.edu (L.H.).

ABSTRACT
Lung cancer has long been recognized as an extremely heterogeneous disease, since its development is unique in every patient in terms of clinical characterizations, prognosis, response and tolerance to treatment. Personalized medicine refers to the use of markers to predict which patient will most likely benefit from a treatment. In lung cancer, the well-developed epidermal growth factor receptor (EGFR) and the newly emerging EML4-anaplastic lymphoma kinase (ALK) are important therapeutic targets. This review covers the basic mechanism of EGFR and EML4-ALK activation, the predictive biomarkers, the mechanism of resistance, and the current targeted tyrosine kinase inhibitors. The efficacy of EGFR and ALK targeted therapies will be discussed in this review by summarizing the prospective clinical trials, which were performed in biomarker-based selected patients. In addition, the revolutionary sequencing and systems strategies will also be included in this review since these technologies will provide a comprehensive understanding in the molecular characterization of cancer, allow better stratification of patients for the most appropriate targeted therapies, eventually resulting in a more promising personalized treatment. The relatively low incidence of EGFR and ALK in non-Asian patients and the lack of response in mutant patients limit the application of the therapies targeting EGFR or ALK. Nevertheless, it is foreseeable that the sequencing and systems strategies may offer a solution for those patients.

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Related in: MedlinePlus

Epidermal growth factor receptor (EGFR). The binding between EGFR and ligand triggers downstream intracellular signaling pathways including the PI3K/AKT prosurvival, STAT transcription, and RAS/RAF/MEK proliferation pathways. The anaplastic lymphoma kinase (ALK) fusion proteins mainly activate the RAS/RAF/MEK and PI3K/AKT pathways. Amplification of the EGFR and ALK signaling pathways drives cell proliferation, cell motility, and carcinogenesis.
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f1-ijms-13-11471: Epidermal growth factor receptor (EGFR). The binding between EGFR and ligand triggers downstream intracellular signaling pathways including the PI3K/AKT prosurvival, STAT transcription, and RAS/RAF/MEK proliferation pathways. The anaplastic lymphoma kinase (ALK) fusion proteins mainly activate the RAS/RAF/MEK and PI3K/AKT pathways. Amplification of the EGFR and ALK signaling pathways drives cell proliferation, cell motility, and carcinogenesis.

Mentions: EGFR is a member of the ErbB family of cell surface receptor tyrosine kinase (RTK). The EGFR family consists of four members: EGFR (or ErbB-1), HER-2 (or ErbB-2), HER-3 (or ErbB-3), and HER-4 (or ErbB4) [14]. It has been demonstrated that RTKs play a crucial role in tumorigenesis by controlling signal transduction pathways that regulate proliferation and apoptosis [15]. The RTKs (with the exception of HER-2) are activated by the binding of specific activating soluble ligands, which occur in the extracellular portion of the RTKs [16]. This interaction between ligands and receptors promotes the formation of functional active homodimers (EGFR dimer) or heterodimers (HER3 or HER4 dimer). It also activates the intracellular kinase domain and a subsequent ATP-dependent cross-autophosphorylation of C-terminal tail of the receptor [14,17]. Eventually, the phosphorylated residues recruit a diverse set of cytoplasmic signaling molecules as a docking site, which triggers downstream intracellular signaling pathways including the PI3K/AKT prosurvival, STAT transcription, and RAS/RAF/MEK proliferation pathways (Figure 1) [18,19]. It is virtually sufficient to deregulate the signaling pathways by stimulating apoptosis and growth cessation [19,20]. In NSCLC patients, 50%–80% have shown an over-expression of EGFR [21], which is associated with angiogenesis and poor prognosis [22]. The association between EGFR alteration and pathogenesis makes it a prime candidate for targeted treatments.


Personalized targeted therapy for lung cancer.

Wu K, House L, Liu W, Cho WC - Int J Mol Sci (2012)

Epidermal growth factor receptor (EGFR). The binding between EGFR and ligand triggers downstream intracellular signaling pathways including the PI3K/AKT prosurvival, STAT transcription, and RAS/RAF/MEK proliferation pathways. The anaplastic lymphoma kinase (ALK) fusion proteins mainly activate the RAS/RAF/MEK and PI3K/AKT pathways. Amplification of the EGFR and ALK signaling pathways drives cell proliferation, cell motility, and carcinogenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472758&req=5

f1-ijms-13-11471: Epidermal growth factor receptor (EGFR). The binding between EGFR and ligand triggers downstream intracellular signaling pathways including the PI3K/AKT prosurvival, STAT transcription, and RAS/RAF/MEK proliferation pathways. The anaplastic lymphoma kinase (ALK) fusion proteins mainly activate the RAS/RAF/MEK and PI3K/AKT pathways. Amplification of the EGFR and ALK signaling pathways drives cell proliferation, cell motility, and carcinogenesis.
Mentions: EGFR is a member of the ErbB family of cell surface receptor tyrosine kinase (RTK). The EGFR family consists of four members: EGFR (or ErbB-1), HER-2 (or ErbB-2), HER-3 (or ErbB-3), and HER-4 (or ErbB4) [14]. It has been demonstrated that RTKs play a crucial role in tumorigenesis by controlling signal transduction pathways that regulate proliferation and apoptosis [15]. The RTKs (with the exception of HER-2) are activated by the binding of specific activating soluble ligands, which occur in the extracellular portion of the RTKs [16]. This interaction between ligands and receptors promotes the formation of functional active homodimers (EGFR dimer) or heterodimers (HER3 or HER4 dimer). It also activates the intracellular kinase domain and a subsequent ATP-dependent cross-autophosphorylation of C-terminal tail of the receptor [14,17]. Eventually, the phosphorylated residues recruit a diverse set of cytoplasmic signaling molecules as a docking site, which triggers downstream intracellular signaling pathways including the PI3K/AKT prosurvival, STAT transcription, and RAS/RAF/MEK proliferation pathways (Figure 1) [18,19]. It is virtually sufficient to deregulate the signaling pathways by stimulating apoptosis and growth cessation [19,20]. In NSCLC patients, 50%–80% have shown an over-expression of EGFR [21], which is associated with angiogenesis and poor prognosis [22]. The association between EGFR alteration and pathogenesis makes it a prime candidate for targeted treatments.

Bottom Line: Personalized medicine refers to the use of markers to predict which patient will most likely benefit from a treatment.In lung cancer, the well-developed epidermal growth factor receptor (EGFR) and the newly emerging EML4-anaplastic lymphoma kinase (ALK) are important therapeutic targets.Nevertheless, it is foreseeable that the sequencing and systems strategies may offer a solution for those patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA; E-Mails: kwu@bsd.uchicago.edu (K.W.); lhouse@medicine.bsd.uchicago.edu (L.H.).

ABSTRACT
Lung cancer has long been recognized as an extremely heterogeneous disease, since its development is unique in every patient in terms of clinical characterizations, prognosis, response and tolerance to treatment. Personalized medicine refers to the use of markers to predict which patient will most likely benefit from a treatment. In lung cancer, the well-developed epidermal growth factor receptor (EGFR) and the newly emerging EML4-anaplastic lymphoma kinase (ALK) are important therapeutic targets. This review covers the basic mechanism of EGFR and EML4-ALK activation, the predictive biomarkers, the mechanism of resistance, and the current targeted tyrosine kinase inhibitors. The efficacy of EGFR and ALK targeted therapies will be discussed in this review by summarizing the prospective clinical trials, which were performed in biomarker-based selected patients. In addition, the revolutionary sequencing and systems strategies will also be included in this review since these technologies will provide a comprehensive understanding in the molecular characterization of cancer, allow better stratification of patients for the most appropriate targeted therapies, eventually resulting in a more promising personalized treatment. The relatively low incidence of EGFR and ALK in non-Asian patients and the lack of response in mutant patients limit the application of the therapies targeting EGFR or ALK. Nevertheless, it is foreseeable that the sequencing and systems strategies may offer a solution for those patients.

Show MeSH
Related in: MedlinePlus