Abstract A290: Kinase activity in vemurafenib-sensitive and resistant BRAF-mutant melanoma cells.

Abstract

Abstract In advanced melanoma, therapeutic targeting of the MAPK signaling pathway with vemurafenib, a potent inhibitor of the BRAFV600E-encoded signaling molecule, commonly results in rapid and substantial tumor responses, but limited durability of the clinical benefit. Therapy resistance inevitably develops either via reactivation of the MAPK (RAF/MEK/ERK) pathway or via bypass mechanisms, such as PI3K/AKT/mTOR-mediated signaling; however, no one mechanism of resistance has been consistently observed on disease progression. In preclinical models, dual inhibition of the MAPK pathway (by MEK inhibitors) and PI3K/AKT/mTOR signaling has shown to be an effective strategy at overcoming this type of resistance, and clinical studies are ongoing. Hypothesizing that different patterns of composite kinase signaling activities in BRAF-mutant melanoma may reflect the response of vemurafenib and other inhibitors (e.g. MEK and AKT inhibitors), we analyzed the tyrosine kinase activity profiles generated by a vemurafenib sensitive melanoma cell line to a vemurafenib resistant melanoma cell line, both harbouring the BRAFV600E mutation. Of note, both cell lines were derived from metastatic tumor biopsies sampled from a patient with disseminated melanoma disease, participating in the BRIM-2 trial, before commencing vemurafenib treatment and at six weeks on treatment. The patient experienced partial therapy response lasting for 15 weeks before disease progression. Interestingly, overall kinase activity was lower in the vemurafenib-resistant cell line, and the phosphorylation levels of a number of array substrates representing mediators of the MAPK and PI3K/AKT/mTOR signaling pathways were different in the cell lines sensitive and resistant to vemurafenib. Whilst treatment with vemurafenib, the MEK inhibitor U0126 and the AKT inhibitor M2266 resulted in limited effect in the vemurafenib-resistant cells, the drugs caused decreased in vitro cell viability in the vemurafenib-sensitive cell line. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A290. Citation Format: Karianne Risberg, Kathrine Røe, Anne H. Ree. Kinase activity in vemurafenib-sensitive and resistant BRAF-mutant melanoma cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A290.