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Updated: May 6, 2026
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Challenging resistance mechanisms to therapies for metastatic melanoma
Lucio Tentori1, Pedro Miguel Lacal, Grazia Graziani
1Department of System Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.
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.
Insights
Metastatic melanoma treatment is improving with new therapies. Combining treatments targeting melanoma cell growth and immune responses may overcome resistance and improve patient outcomes.
Area of Science:
- Oncology
- Immunology
- Dermatology
Background:
- Melanoma is an aggressive skin cancer with poor prognosis once metastatic.
- Current treatments like ipilimumab and BRAF inhibitors offer limited long-term benefit for most patients.
Purpose of the Study:
- To review current and emerging combination therapies for metastatic melanoma.
- To discuss strategies for overcoming treatment resistance by targeting both cancer cells and the immune system.
Main Methods:
- Review of existing literature on melanoma treatment modalities.
- Analysis of preclinical and clinical data on combination therapies.
- Discussion of targeted agents and immunomodulators.
Main Results:
- While ipilimumab and BRAF inhibitors have shown efficacy, responses are often short-lived.
- Combination therapies involving DNA repair inhibitors, novel immunomodulators (PD-1/PD-L1), targeted therapies (MEK, PI3K/AKT/mTOR), and antiangiogenic agents are under investigation.
- Simultaneous targeting of melanoma proliferation/survival and immune responses is a promising strategy.
Conclusions:
- Improved efficacy in melanoma treatment requires overcoming resistance mechanisms.
- Combination therapies hold potential for achieving durable clinical benefit in metastatic melanoma.
- Targeting both tumor cell-intrinsic pathways and the tumor immune microenvironment is crucial.
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