The Potential of Targeting P53 and HSP90 Overcoming Acquired MAPKi-Resistant Melanoma

Curr Treat Options Oncol. 2019 Feb 18;20(3):22. doi: 10.1007/s11864-019-0622-9.

Abstract

Melanoma is the deadliest form of skin cancer worldwide. The rising melanoma incidence and mortality, along with its high propensity for metastasis highlights the urgency to identify more effective therapeutic targets. Approximately, one half of advanced melanoma bears a mutation in the BRAF gene that makes BRAF as an important therapeutic target. Significant clinical benefit is associated with BRAF and MEK inhibitors (MAPKi) on targeting patients with BRAF V600 mutations. However, the frequent and rapid development of acquired resistance still is the major challenge facing the melanoma. Several mechanisms by which melanoma passes the inhibitory effects of MAPKi have been characterized and clinically translated, but additional alternations of genetic and epigenetic regulators outside of MAPK and/or AKT networks occurs in a quarter of patients with acquired MAPKi resistance. These studies implicate that targeting signaling networks external MAPK or AKT pathways is critical. In this review, we will focus on two approaches that are under evaluating for targeting melanoma: (1) against genome instability by p53 network restoration and (2) disrupt cancer proteome by chaperone inhibition.

Keywords: BRAF; HSP90; Melanoma; p53.

Publication types

  • Review

MeSH terms

  • Drug Resistance, Neoplasm / drug effects*
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Humans
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / pathology
  • Molecular Targeted Therapy*
  • Mutation
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins B-raf / drug effects
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology
  • Treatment Outcome
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*

Substances

  • HSP90 Heat-Shock Proteins
  • Protein Kinase Inhibitors
  • Tumor Suppressor Protein p53
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf