Effect of the farnesyl transferase inhibitor lonafarnib on sensitivity of melanoma cells to the multikinase inhibitor sorafenib and on Rheb farnesylation and mTOR signaling
9077 Background: Farnesyl transferase inhibitors (FTIs) inhibit the post-translational farnesylation of a number of target proteins, including Ras and Rheb, preventing their signaling function. Ras signals to the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR (AKT) signaling pathways which are constitutively activated in melanoma and appear to play a major role in tumor progression and drug resistance. Rheb positively regulates mTOR signaling. Methods: Using a panel of melanoma cell lines we evaluated the effects of the FTI lonafarnib alone and in combination with chemotherapeutic agents (temozolomide, cisplatin) or pharmacological MAPK pathway inhibitors (sorafenib, U0126, PD98059) or AKT pathway inhibitors (LY294002, wortmannin, rapamycin) on proliferation, survival and invasive tumor growth of melanoma cells in monolayer and organotypic culture. Results: Lonafarnib did not significantly inhibit growth of metastatic melanoma cells. Also, lonafarnib did not sensitize melanoma cells to the chemotherapeutic agents tested. Most combinations of the FTI lonafarnib with MAPK or AKT pathway inhibitors lacked significant enhancement of growth inhibition compared to monotherapy. In contrast, lonafarnib significantly augmented the growth inhibitory effects of the multikinase inhibitor sorafenib in eight metastatic melanoma cell lines tested. These effects did not appear to depend on BRAF or NRAS mutation status. Moreover, lonafarnib combined with sorafenib induced marked apoptosis and abrogated invasive melanoma growth. Interestingly, the FTI lonafarnib did not inhibit phosphorylation of ERK or AKT but of p70S6K, a downstream target of Rheb and mTOR signaling. Conclusions: These data suggest that lonafarnib sensitizes melanoma cells to sorafenib by inhibiting mTOR signaling via inhibition of Rheb farnesylation. No significant financial relationships to disclose.