Non-Small Cell Lung Cancer Signaling Pathways
Approximately 10% of patients with non-small cell lung cancer (NSCLC) have an abnormality involving Epidermal Growth Factor Receptor (EGFR). The presence of an EGFR abnormality may have a significant effect on how your cancer responds to anti-EGFR therapy. In addition, as shown in the illustration, the molecular pathways by which EGFR abnormalities drive cancer development are extremely complex and involve many interconnected signaling pathways, including both signaling molecules (such as Ras and PI3K) and receptors (such as MET and HER-2). Abnormalities in the function of these signaling molecules and receptors can also dramatically influence how your cancer will respond to anti-EGFR therapy as well as other molecular targeted therapies that target different components within the EGFR and related pathways.
For this reason, additional diagnostic testing may be necessary to provide greater insight into the molecular profile of your cancer. These diagnostic tests are designed to identify signs of abnormalities in both receptors and signaling molecules, referred to as biomarkers, which can help your physician determine the most precise and effective treatment strategy available for your specific cancer. |
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The Ras oncogenes are a family of genes that have been implicated in cancer. Perhaps the best-studied member is K-ras, which encodes a signaling molecule, Ras, that functions downstream of EGFR. When EGFR is activated, it passes the signal on to Ras, which in turn sends the signal on through other proteins to promote cell proliferation. Mutations in K-ras occur in approximately 10% of NSCLC tumors, largely in adenocarcinomas (31). A mutation in the K-ras gene causes Ras to be constantly activated, which causes cell proliferation and tumor formation.
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Non-Small Cell Lung Cancer Signaling Pathways Overview
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PI3K and Akt are part of an important signaling pathway downstream of EGFR: An activated EGFR sends a signal to the protein PI3K, which in turn propagates the signal and causes the phosphorylation of (the addition of a phosphate molecule to) the protein Akt. The phosphorylation of Akt generates p-Akt, an activated form of Akt that promotes cell survival and proliferation. Too much PI3K/p-Akt signaling can promote tumor growth.
Another protein, called PTEN, acts in opposition to the PI3K/Akt pathway by reversing the activity of PI3K. Thus, either overactivation of PI3K or p-Akt or inactivation of PTEN will cause uncontrolled cell growth and tumor formation. Because the PI3K pathway is controlled by EGFR, the pathway is continuously activated in tumors in which EGFR is activated (39).
Learn more about PI3K biomarkers and targeted therapy
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Non-Small Cell Lung Cancer Signaling Pathways Overview
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PPARγ is a protein involved in regulating the PI3K/Akt pathway (which drives tumor growth). It carries out this function by controlling the activation of a gene called PTEN, a tumor-suppressor gene that inhibits the PI3K/Akt signaling pathway. In other words, when PPAR and PTEN are active, tumor growth is suppressed; when PPAR and PTEN are inactive, tumor growth is encouraged.
Learn more about PPARγ biomarkers and targeted therapy
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Non-Small Cell Lung Cancer Signaling Pathways Overview
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MET is a receptor, like EGFR, that receives signals from the environment and passes them on to the interior of the cell. When MET is activated, it signals other pathways, including PI3K/Akt and Ras, which results in cell growth and other cellular responses. Mutations and amplifications in the gene for MET have been identified in several types of cancer (56). In addition, MET amplification has been implicated as a mechanism by which cancer cells acquire resistance to EGFR inhibitors (11).
Learn more about MET biomarkers and targeted therapy
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Non-Small Cell Lung Cancer Signaling Pathways Overview
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