title: Challenging resistance mechanisms to therapies for metastatic melanoma.
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.
authors.affiliation: Department of System Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Tentori
authors.forename: Pedro Miguel
authors.initials: PM
authors.lastname: Lacal
authors.forename: Grazia
authors.initials: G
authors.lastname: Graziani
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D000074324:Ipilimumab; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology*; D009362:Neoplasm Metastasis; D010091:Oximes / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: D000911:Antibodies, Monoclonal; D007093:Imidazoles; D007211:Indoles; D000074324:Ipilimumab; D010091:Oximes; D013449:Sulfonamides; D000077484:Vemurafenib; C561627:dabrafenib
keywords: BRAF inhibitors; immunotherapy; ipilimumab; poly(ADP-ribose) polymerase (PARP) inhibitors; temozolomide; vemurafenib