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    Molecular therapeutic advances in personalized therapy of melanoma and non-small cell lung cancer.

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    6
    Author
    Kelleher, FC; Solomon, B; McArthur, GA
    Date
    2012-04-10
    Source Title
    Journal of Personalized Medicine
    Publisher
    MDPI AG
    University of Melbourne Author/s
    Solomon, Benjamin; McArthur, Grant
    Affiliation
    Medicine and Radiology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Kelleher, F. C., Solomon, B. & McArthur, G. A. (2012). Molecular therapeutic advances in personalized therapy of melanoma and non-small cell lung cancer.. J Pers Med, 2 (2), pp.35-49. https://doi.org/10.3390/jpm2020035.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/259516
    DOI
    10.3390/jpm2020035
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251364
    Abstract
    The incorporation of individualized molecular therapeutics into routine clinical practice for both non-small cell lung cancer (NSCLC) and melanoma are amongst the most significant advances of the last decades in medical oncology. In NSCLC activating somatic mutations in exons encoding the tyrosine kinase domain of the Epidermal Growth Factor Receptor (EGFR) gene have been found to be predictive of a response to treatment with tyrosine kinase inhibitors (TKI), erlotinib or gefitinib. More recently the EML4-ALK fusion gene which occurs in 3-5% of NSCLC has been found to predict sensitivity to crizotinib an inhibitor of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase. Similarly in melanoma, 50% of cases have BRAF mutations in exon 15 mostly V600E and these cases are sensitive to the BRAF inhibitors vemurafenib or dabrafenib. In a Phase III study of advanced melanoma cases with this mutation vemurafenib improved survival from 64% to 84% at 6 months, when compared with dacarbazine. In both NSCLC and melanoma clinical benefit is not obtained in patients without these genomic changes, and moreover in the case of vemurafenib the therapy may theoretically induce proliferation of cases of melanoma without BRAF mutations. An emerging clinical challenge is that of acquired resistance after initial responses to targeted therapeutics. Resistance to the TKI's in NSCLC is most frequently due to acquisition of secondary mutations within the tyrosine kinase of the EGFR or alternatively activation of alternative tyrosine kinases such as C-MET. Mechanisms of drug resistance in melanoma to vemurafenib do not involve mutations in BRAF itself but are associated with a variety of molecular changes including RAF1 or COT gene over expression, activating mutations in RAS or increased activation of the receptor tyrosine kinase PDGFRβ. Importantly these data support introducing re-biopsy of tumors at progression to continue to personalize the choice of therapy throughout the patient's disease course.

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