Browsing Theses and Dissertations School of Pharmacy by Author "Samadani, Ramin"
Overcoming Drug Resistance in BRaf Mutated Melanoma CellsSamadani, Ramin; Shapiro, Paul, Ph.D. (2015)Targeted inhibition of the ERK1/2 signaling pathway has received much attention after the transient success of the BRaf inhibitor, vemurafenib, in metastatic melanoma patients with the BRafV600E mutation. Approximately 50% of melanomas have an activating mutation to BRaf which drives cancer cell proliferation and survival through the ERK1/2 pathway. Therapies targeting BRaf or its downstream kinase MEK1/2 have demonstrated very promising initial clinical results. However, these treatments invariably lead to drug resistance through the activation of alternate pathways or mutations that circumvent the blockade and reactivate ERK1/2. Current efforts are centered on the use of combination therapies as well as the direct inhibition of ERK1/2 itself. The purpose of these studies is to characterize putative substrate-selective ERK inhibitors and examine their effects in various clinically relevant models of drug resistance. Specifically melanoma cell lines resistant to BRaf and MEK inhibitors, PLX-4032 and AZD-6244 respectively, were generated to test the efficacy of these novel compounds in cell viability assays. Furthermore, the potency of these molecules was evaluated in drug resistant cell lines that overexpress MAP3K8 (the gene encoding COT/Tpl2). The data show that these putative substrate-selective ERK inhibitors preferentially inhibit proliferation of cell lines with activated ERK1/2 signaling. In addition, these novel molecularly targeted therapies are equipotent in drug resistant versus non-resistant melanoma cells. Given these compounds' selectivity for BRaf mutated melanoma cells and their efficacy in drug resistance models, we submit these novel chemical entities as potential lead candidates for new salvage therapies in patients who have become resistant to currently available treatments. Moreover, these ATP-independent inhibitors target only select ERK1/2 functions and may be inherently less susceptible to developing their own drug resistance as compared to complete ablation of all ERK1/2 signaling as seen with ATP-competitive inhibitors.