Genotype-Selective Combination Therapies for Melanoma Identified by High-Throughput Drug Screening

Departments of 1Pathology and 2Dermatology, Yale University School of Medicine, New Haven, Connecticut.
Cancer Discovery (Impact Factor: 19.45). 12/2012; 3(1). DOI: 10.1158/2159-8290.CD-12-0408
Source: PubMed

ABSTRACT Resistance and partial responses to targeted monotherapy are major obstacles in cancer treatment. Systematic approaches to identify efficacious drug combinations for cancer are not well established, especially in the context of genotype. To address this, we have tested pairwise combinations of an array of small-molecule inhibitors on early-passage melanoma cultures using combinatorial drug screening. Results reveal several inhibitor combinations effective for melanomas with activating RAS or BRAF mutations, including mutant BRAF melanomas with intrinsic or acquired resistance to vemurafenib. Inhibition of both EGF receptor and AKT sensitized treatment-resistant BRAF mutant melanoma cultures to vemurafenib. Melanomas with RAS mutations were more resistant to combination therapies relative to BRAF mutants, but were sensitive to combinations of statins and cyclin-dependent kinase inhibitors in vitro and in vivo. These results show the use of combinatorial drug screening for discovering unique treatment regimens that overcome resistance phenotypes of mutant BRAF- and RAS-driven melanomas.

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    • "Dasatinib, an inhibitor of BCR-Abl kinase and SRC kinase, exhibited synergistic growth inhibition with afatinib in NSCLC lines expressing L858R/T790M or the combination of del E746-A750 with a deletion of exon 9 in PTEN (Chang and Wang 2012). In BRAF mutant melanoma cell lines, afatinib also had a little effect as a single agent but became a more potent growth inhibitor in the presence of Akt inhibitors (GSK690693 and MK-2206) (Held et al. 2013). Pfeifer and colleagues have systematically explored the compound combination PI-103 (dual PI3K/mTOR inhibitor) with afatinib on a panel of 65 NSCLC cell lines (Pfeifer et al. 2010). "
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    • "Pooled screens have recently been described to screen synergistic combinations for treatment of HIV and could be adapted to screen cancer cell lines (Tan et al., 2012). Recently, a genotype– phenotype combination screen has been completed in melanoma (Held et al., 2013), which demonstrated the utility of these approaches, although definitive evaluation of the results in additional preclinical (and clinical) scenarios is needed. "
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