Abstract 5523: Study of the response of melanoma lines to BRAF/MEK inhibitors and combination drug treatments

The serine-threonine protein kinase, BRAF, is a frequently mutated oncogene, found in cancers of the skin, thyroid and large intestine. It is especially prevalent in malignant melanoma, where it occurs in 40-60% of the cases. The most common BRAF mutation is the valine to glutamate substitution at position 600 of the kinase (V600E). This substitution, seen in ninety percent of the BRAF cases, leads to constitutive activation of the kinase, and the downstream MEK-ERK pathway. Appropriately, several drugs have been designed to inhibit BRAF, with a broad range of outcomes in clinical trials. Unfortunately, all patients, including those showing complete responses, develop resistance to single agent therapy. Our goal is to come up with effective drug combinations that would delay, or even prevent, the cancer from becoming resistant to treatment. We used a panel of 43 melanoma lines, comprising of 28 BRAF mutants, 12 NRAS mutants and 3 lines that were wild type for these two genes. Besides BRAF and NRAS, we have the mutational status of 65 other commonly mutated cancer genes for all the lines. We assembled a set of 25 drugs targeting a wide range of proteins, including PI3K/mTOR inhibitors, the apoptosis machinery, as well as some epigenetic modulators. The melanoma lines were treated with these drugs, either (i) alone or (ii) in combination with the B-RAF inhibitor vemurafenib or (iii) in combination with the MEK inhibitor Selumetinib, for 72 hrs over a nine point, 256-fold concentration range. Viability and apoptosis were measured using cell titer glo (Promega). The results from this pilot study are discussed here. Note: This abstract was not presented at the meeting. Citation Format: Anahita Dastur, Cyril Benes. Study of the response of melanoma lines to BRAF/MEK inhibitors and combination drug treatments. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5523. doi:10.1158/1538-7445.AM2014-5523