Targeting Prohibitins to Inhibit Melanoma Growth and Overcome Resistance to Targeted Therapies

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Metastatic melanoma treatment faces challenges with therapy resistance and lack of options for BRAF wild-type cases.
• Prohibitins (PHBs) are implicated in cancer progression, invasion, and apoptosis resistance.
• PHB overexpression in melanoma correlates with poor survival and resistance to MAPK-targeted inhibitors (MAPKi).

Purpose of the Study:

• To investigate the therapeutic potential of targeting prohibitins in melanoma.
• To develop and evaluate novel PHB inhibitors for melanoma treatment, including resistant and BRAF wild-type subtypes.

Main Methods:

• Design and identification of specific PHB inhibitors.
• Evaluation of PHB inhibitors in 3D spheroid and cell line models representing diverse melanoma subtypes.
• Assessment of molecular pathway modulation (MAPK, PI3K/AKT), apoptosis induction, and combination therapy effects (with MAPKi and autophagy inhibitors).

Main Results:

• PHB inhibitors effectively reduced melanoma cell growth across various subtypes, including those resistant to MAPKi.
• Inhibitors moderated MAPK and PI3K/AKT pathways, induced apoptosis via the mitochondrial pathway, and upregulated p53.
• Combined inhibition of PHB and autophagy enhanced antitumor effects.
• PHB inhibitors synergized with MAPKi to overcome drug resistance in both BRAF wild-type and mutant melanoma.

Conclusions:

• Targeting prohibitins is a promising therapeutic strategy for melanoma, irrespective of BRAF mutational status.
• Novel PHB inhibitors demonstrate potential for treating drug-resistant and BRAF wild-type melanoma.
• Combination strategies involving PHB inhibitors offer enhanced efficacy and resistance overcoming capabilities.