Does parthenolide overcome vemurafenib resistance by inhibiting heat shock protein 90 in melanoma?

Malignant melanoma is aggressive and has a high mortality rate. About 50% of melanoma patients carry a BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutation of valine 600 to glutamine (V600E). Although targeted therapies with selective BRAF(V600E) inhibitors, such as vemurafenib, have shown remarkable clinical efficacy in patients with BRAF(V600E)-mutant melanomas, most patients develop resistance within 5 to 8 months. Heat shock protein 90 (Hsp90) is a chaperone of diverse oncoproteins playing a key role in the acquired resistance in melanoma. In cancer cells, Hsp90 presents a high binding affinity state, which may drive selective accumulation of Hsp90 inhibitors in tumors. Therefore, Hsp90 has been proposed as a good target for overcoming resistance to selective BRAF(V600E) inhibitors in melanoma. However, current Hsp90 inhibitors have various limitations such as instability and toxicity. Novel Hsp90 inhibiting agents for treating BRAF(V600E) inhibitor-resistant melanomas are needed. Some parthenolide-containing Chinese medicinal herbs such as Flos Chrysanthemi and Cortex Magnoliae Officinalis are commonly prescribed for melanoma management. By molecular docking-based screening, we found that parthenolide binds Hsp90α (the inducible/major isoform of Hsp90) at its ATP-binding site. Further, parthenolide dose-dependently inhibits ATPase activity of Hsp90α, lowers levels of Hsp90 client proteins and reduces cell viability in vemurafenib-resistant melanoma cells. Importantly, we found that prophylactic dosing of parthenolide significantly inhibits tumor growth in vemurafenib-resistant melanoma cell-bearing mice (immediately after cell implantation, 1 or 2 mg/kg/day of parthenolide, i.p. for 31 days). We, therefore, hypothesize that parthenolide overcomes vemurafenib resistance in melanoma by inhibiting Hsp90. To prove this hypothesis, we propose:
1) to confirm that parthenolide can overcome vemurafenib resistance, and to monitor toxicities of parthenolide in melanoma-bearing mice;
2) to establish the role of Hsp90 in the effect of parthenolide for overcoming vemurafenib resistance in melanoma cells;
3) to determine whether parthenolide preferentially binds Hsp90 derived from vemurafenib-resistant melanoma cells/tissues; and
4) to determine whether parthenolide overcomes resistance to other BRAF(V600E)-targeted therapies in melanoma cells.

This study will for the first time demonstrate the ability of parthenolide to overcome vemurafenib resistance via, at least in part, inhibiting Hsp90 in BRAF(V600E)-mutant melanomas. This contribution will be significant because it is one step in a continuum of research that is expected to lead to the development of parthenolide as a novel agent for curing vemurafenib-resistant melanomas