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Systemic treatment in EGFR-ALK NSCLC patients: second line therapy and beyond.

Karachaliou N, Rosell R - Cancer Biol Med (2014)

Bottom Line: Deeper understanding of the pathobiology of non-small cell lung cancer (NSCLC) has led to the development of small molecules that target genetic mutations known to play critical roles in progression to metastatic disease and to influence response to targeted therapies.The principle goal of precision medicine is to define those patient populations most likely to respond to targeted therapies.However, the cancer genome landscape is composed of relatively few "mountains" [representing the most commonly mutated genes like KRAS, epidermal growth factor (EGFR), and anaplastic lymphoma kinase (ALK)] and a vast number of "hills" (representing low frequency but potentially actionable mutations).

View Article: PubMed Central - PubMed

Affiliation: 1 Translational Research Unit, Dr Rosell Oncology Institute, Quirón Dexeus University Hospital, 08028 Barcelona, Spain ; 2 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet s/n, 08916 Badalona, Barcelona, Spain ; 3 Fundación Molecular Oncology Research (MORe), Sabino Arana 5-19, 08028 Barcelona, Spain.

ABSTRACT
Lung cancer is the most frequently diagnosed cancer and a leading cause of cancer mortality worldwide, with adenocarcinoma being the most common histological subtype. Deeper understanding of the pathobiology of non-small cell lung cancer (NSCLC) has led to the development of small molecules that target genetic mutations known to play critical roles in progression to metastatic disease and to influence response to targeted therapies. The principle goal of precision medicine is to define those patient populations most likely to respond to targeted therapies. However, the cancer genome landscape is composed of relatively few "mountains" [representing the most commonly mutated genes like KRAS, epidermal growth factor (EGFR), and anaplastic lymphoma kinase (ALK)] and a vast number of "hills" (representing low frequency but potentially actionable mutations). Low-frequency lesions that affect a druggable gene product allow a relatively small population of cancer patients for targeted therapy to be selected.

No MeSH data available.


Related in: MedlinePlus

EML4-ALK signaling pathways and potential mechanisms of resistance to targeted therapies. EML4-ALK, echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinase.
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f2: EML4-ALK signaling pathways and potential mechanisms of resistance to targeted therapies. EML4-ALK, echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinase.

Mentions: ALK and its ligand pleiotrophin are required for self-renewal and tumorigenicity of glioblastoma stem cells (GSCs)58. The pleiotrophin-ALK axis is activated by SOX2 and may be a promising target for therapy in ALK signaling-dependent tumors58. Finally, Takezawa et al. demonstrated that expression of BIM and survivin are independently regulated by ERK and STAT3 signaling pathways, respectively, and are implicated in ALK-TKI-induced apoptosis in NSCLC cells positive for EML4-ALK59. A selective inhibitor of ALK kinase activity (more potent than crizotinib), NVP-TAE68, inhibits STAT3 phosphorylation and downregulates survivin in H2228 cells, but fails to inhibit ERK phosphorylation and upregulate BIM. In a recent study, inhibition of both STAT3 and ERK pathways with the combination of TAE684 and a MEK inhibitor, AZD6244, was associated with a marked increase in the number of apoptotic cells60 (Figure 2).


Systemic treatment in EGFR-ALK NSCLC patients: second line therapy and beyond.

Karachaliou N, Rosell R - Cancer Biol Med (2014)

EML4-ALK signaling pathways and potential mechanisms of resistance to targeted therapies. EML4-ALK, echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4197428&req=5

f2: EML4-ALK signaling pathways and potential mechanisms of resistance to targeted therapies. EML4-ALK, echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinase.
Mentions: ALK and its ligand pleiotrophin are required for self-renewal and tumorigenicity of glioblastoma stem cells (GSCs)58. The pleiotrophin-ALK axis is activated by SOX2 and may be a promising target for therapy in ALK signaling-dependent tumors58. Finally, Takezawa et al. demonstrated that expression of BIM and survivin are independently regulated by ERK and STAT3 signaling pathways, respectively, and are implicated in ALK-TKI-induced apoptosis in NSCLC cells positive for EML4-ALK59. A selective inhibitor of ALK kinase activity (more potent than crizotinib), NVP-TAE68, inhibits STAT3 phosphorylation and downregulates survivin in H2228 cells, but fails to inhibit ERK phosphorylation and upregulate BIM. In a recent study, inhibition of both STAT3 and ERK pathways with the combination of TAE684 and a MEK inhibitor, AZD6244, was associated with a marked increase in the number of apoptotic cells60 (Figure 2).

Bottom Line: Deeper understanding of the pathobiology of non-small cell lung cancer (NSCLC) has led to the development of small molecules that target genetic mutations known to play critical roles in progression to metastatic disease and to influence response to targeted therapies.The principle goal of precision medicine is to define those patient populations most likely to respond to targeted therapies.However, the cancer genome landscape is composed of relatively few "mountains" [representing the most commonly mutated genes like KRAS, epidermal growth factor (EGFR), and anaplastic lymphoma kinase (ALK)] and a vast number of "hills" (representing low frequency but potentially actionable mutations).

View Article: PubMed Central - PubMed

Affiliation: 1 Translational Research Unit, Dr Rosell Oncology Institute, Quirón Dexeus University Hospital, 08028 Barcelona, Spain ; 2 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet s/n, 08916 Badalona, Barcelona, Spain ; 3 Fundación Molecular Oncology Research (MORe), Sabino Arana 5-19, 08028 Barcelona, Spain.

ABSTRACT
Lung cancer is the most frequently diagnosed cancer and a leading cause of cancer mortality worldwide, with adenocarcinoma being the most common histological subtype. Deeper understanding of the pathobiology of non-small cell lung cancer (NSCLC) has led to the development of small molecules that target genetic mutations known to play critical roles in progression to metastatic disease and to influence response to targeted therapies. The principle goal of precision medicine is to define those patient populations most likely to respond to targeted therapies. However, the cancer genome landscape is composed of relatively few "mountains" [representing the most commonly mutated genes like KRAS, epidermal growth factor (EGFR), and anaplastic lymphoma kinase (ALK)] and a vast number of "hills" (representing low frequency but potentially actionable mutations). Low-frequency lesions that affect a druggable gene product allow a relatively small population of cancer patients for targeted therapy to be selected.

No MeSH data available.


Related in: MedlinePlus