LUNG CANCER: DRIVER ONCOGENE AND MOLECULAR-TARGETED THERAPIES

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Abstract

Identification of oncogenic genomic alterations is expected to facilitate the development of new molecularly targeted therapies for cancer. The first identified ‘driver oncogene’ directly associated with molecular targeted therapies for non-small-cell lung cancer (NSCLC) is mutated epidermal growth factor receptor (EGFR) which is found in up to 30% of Asian NSCLC patients. Preclinical studies demonstrated that EGFR mutation-positive tumors are dependent on, or ‘addicted’ to, EGFR signaling for their growth and survival and exposure of those tumors to EGFR tyrosine kinase inhibitors (TKIs), thus results in EGFR-signaling pathways being turned off and the cancer cells undergoing apoptosis. These findings did quickly translate into clinical trials. Asian landmark phase III trials have now led to the new paradigm of using EGFR-TKIs such as gefitinib or elrotinib for first-line treatment of EGFR-mutation-positive advanced NSCLC. Such findings indicate that the use of molecularly targeted therapy in genetically defined subsets of NSCLC patients may prove to be an effective strategy.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase whose gene was initially identified as part of the NPM-ALK fusion gene that contributes to the pathogenesis of a subset of anaplastic large cell lymphoma cases. In 2007, a fusion of ALK with the echinoderm microtubule-associated protein-like 4 gene (EML4) was identified by a Japanese group led by Hiroyuki Mano. EML4-ALK undergoes constitutive oligomerization mediated by the coiled-coil domain of the EML4 portion of the fusion protein, and it manifests marked oncogenic activity both in vitro and in vivo. Crizotinib was the first ALK inhibitor to be tested in the clinical setting. On the basis of its dramatic clinical activity, crizotinib was approved by the FDA for treatment of ALK rearrangement-positive NSCLC in August 2011. The promise of molecular targeted drugs against these driver gene alterations brings us closer to personalized lung cancer therapy.

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