Abstract 5487: The requirements for dasatinib sensitivity in human melanoma cell lines

Abstract

Mutated BRAF oncogene, which fuels unregulated MAPK pathway in most melanomas, can be targeted by a small-molecule drug vemurafenib. However, most of patients develop an acquired resistance during treatment or have an intrinsic resistance to this drug. Nonreceptor SRC tyrosine kinase is deregulated in most cancer cell types and can be efficiently inhibited by a small-molecule inhibitor dasatinib, an anticancer drug which is already used for the treatment of some cancers and is in final clinical trials for other tumor types. Although SRC does not have its own canonical pathway, it is capable of activating and augmenting different signaling routes in cancer cells. We found that melanoma tumor cell lines analysed up to date are generally resistant to dasatinib. The exception to this rule was Hbl, a very sensitive cell line whose cells were completely killed by a 10 nM of dasatinib in a few days. The difference in resistance of melanoma cell lines to dasatinib did not depend on primary versus metastatic cell origin or the presence of BRAF or NRAS mutations. Instead, the dasatinib sensitivity was dependent on its ability to inhibit completely both the MAPK and AKT/mTOR signaling pathways. This inhibition was at least as prominent as the inhibition by specific inhibitors of the two pathways. SRC has been reported previously to have links to this signaling pathways with the capacity to inhibit them in some cell types. Moreover, extensive cross-talk exists between the two pathways. Similar results were observed in several other cell lines derived mostly from lung and colorectal cancers. Our data indicate that the singular therapy of melanoma by dasatinib only would bring no benefit to patients, except for the cases (probably rare) where dasatinib strongly blocks both MAPK and AKT signaling pathways in tumor cells. More molecular knowledge about the effects of the powerful anticancer drug dasatinib is required in order to be used for the treatment of melanoma. This work was supported by grant IGA no. NT/14005-3 from the Ministry of Health (Czech Rep.) and by Institutional research project PRVOUK-P25/LF1/2. Citation Format: Jiri Vachtenheim, Jiri Réda, Lubica Ondrušová, Petra Zakova. The requirements for dasatinib sensitivity in human melanoma cell lines. [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 5487. doi:10.1158/1538-7445.AM2014-5487