Parthenolide Inhibits Hsp90α ATPase Activity and Overcomes Acquired BRAF-Inhibitor Resistance in Cutaneous Melanoma

Background: Oncogenic mutations in the BRAF gene, particularly the V600E mutation, are present in roughly half of metastatic cutaneous melanoma cases. BRAF inhibitors (BRAFi) have shown significant clinical efficacy; however, their long-term effectiveness is frequently limited by the development of resistance. Parthenolide, a sesquiterpene lactone derived from medicinal herbs, has previously been reported to exhibit anti-melanoma effects and to disrupt signaling pathways associated with BRAFi resistance.

Purpose: This study aimed to evaluate the potential of parthenolide to overcome resistance to BRAFi in melanoma.

Study Design and Methods: The effects of parthenolide on BRAFi-resistant melanoma cells were assessed using cell viability, apoptosis, and cell cycle assays. In vivo efficacy and safety were evaluated in a BRAFi-resistant melanoma xenograft mouse model. Target identification and validation were performed using network pharmacology, molecular docking, surface plasmon resonance, and Western blotting.

Results: Parthenolide inhibited cell viability and induced apoptosis and S-phase cell cycle arrest in BRAFi-resistant melanoma cells. In vivo, parthenolide significantly suppressed tumor growth and reduced tumor weight in BRAFi-resistant melanoma xenografts without apparent toxicity. Mechanistically, parthenolide stably interacted with the N-terminal ATPase domain of Hsp90α and dose-dependently inhibited its ATPase activity. Hsp90α functions as a chaperone for several oncoproteins involved in signaling pathways driving BRAFi resistance. Parthenolide reduced the levels of several Hsp90α client proteins and inhibited their downstream pathways, including PI3K/Akt, Ras/Raf/MEK, and Src/STAT3, in BRAFi-resistant melanoma cells. Moreover, the Hsp90 activator tamoxifen attenuated the effects of parthenolide in these cells.

Conclusion: Our findings provide the first evidence that parthenolide can overcome BRAFi resistance in melanoma, highlighting its potential as a lead compound for the development of Hsp90α inhibitors to manage BRAFi-resistant cutaneous melanoma.