Challenging resistance mechanisms to therapies for metastatic melanoma

Lucio Tentori, Pedro Miguel Lacal, Grazia Graziani

Research output: Contribution to journalArticle

Abstract

Melanoma is the most aggressive form of skin cancer and, if spread outside the epidermis, has a dismal prognosis. Before the approval of the anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab and the BRAF inhibitors vemurafenib and dabrafenib, no other agents had demonstrated better results in terms of overall survival than the DNA-methylating compound dacarbazine (or its oral analog temozolomide). However, most patients with metastatic melanoma do not obtain long-lasting clinical benefit from ipilimumab and responses to BRAF inhibitors are short lived. Thus, combination therapies with inhibitors of DNA repair (e.g., poly(ADP-ribose) polymerase PARP inhibitors), novel immunomodulators (monoclonal antibodies against programmed death-1 PD-1 or its ligand PD-L1), targeted therapies (mitogen-activated protein kinase [MAPK]/extracellular signal-regulated kinase [ERK] kinase [MEK] or phosphatidylinositol 3-kinase [PI3K]/AKT/mammalian target of rapamycin [mTOR] inhibitors) or antiangiogenic agents are currently being investigated to improve the efficacy of antimelanoma therapies. This review discusses the implications of simultaneously targeting key regulators of melanoma cell proliferation/ survival and immune responses to counteract resistance.

Original languageEnglish
Pages (from-to)656-666
Number of pages11
JournalTrends in Pharmacological Sciences
Volume34
Issue number12
DOIs
Publication statusPublished - Dec 2013

Fingerprint

temozolomide
Melanoma
Monoclonal Antibodies
Phosphatidylinositol 3-Kinase
CTLA-4 Antigen
MAP Kinase Kinase Kinases
Dacarbazine
Angiogenesis Inhibitors
Poly(ADP-ribose) Polymerases
DNA
Extracellular Signal-Regulated MAP Kinases
Cell proliferation
Immunologic Factors
Sirolimus
Mitogen-Activated Protein Kinases
Skin
Repair
Skin Neoplasms
Ligands
Epidermis

Keywords

  • BRAF inhibitors
  • immunotherapy
  • ipilimumab
  • poly(ADP-ribose) polymerase (PARP) inhibitors
  • temozolomide
  • vemurafenib

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Challenging resistance mechanisms to therapies for metastatic melanoma. / Tentori, Lucio; Lacal, Pedro Miguel; Graziani, Grazia.

In: Trends in Pharmacological Sciences, Vol. 34, No. 12, 12.2013, p. 656-666.

Research output: Contribution to journalArticle

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