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Updated: Aug 5, 2025
A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
The therapeutic potential of targeting minimal residual disease in melanoma
Riyaben P Patel1,2, Pretashini M Somasundram3, Lorey K Smith1,2
1Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Background:
Cutaneous melanoma is a lethal form of skin cancer with morbidity and mortality rates highest amongst European, North American and Australasian populations. The developments of targeted therapies (TTs) directed at the oncogene BRAF and its downstream mediator MEK, and immune checkpoint inhibitors (ICI), have revolutionized the treatment of metastatic melanoma, improving patient outcomes. However, both TT and ICI have their limitations. Although TTs are associated with high initial response rates, these are typically short-lived due to resistance. Conversely, although ICIs provide more durable responses, they have lower initial response rates. Due to these distinct yet complementary response profiles, it has been proposed that sequencing ICI with TT could lead to a high frequency of durable responses whilst circumventing the toxicity associated with combined ICI + TT treatment. However, several questions remain unanswered, including the mechanisms underpinning this synergy and the optimal sequencing strategy. The key to determining this is to uncover the biology of each phase of the therapeutic response.
Aims And Methods:
In this review, we show that melanoma responds to TT and ICI in three phases: early response, minimal residual disease (MRD) and disease progression. We explore the effects of ICI and TT on melanoma cells and the tumour immune microenvironment, with a particular focus on MRD which is predicted to underpin the development of acquired resistance in the third phase of response.
Conclusion:
In doing so, we provide a new framework which may inform novel therapeutic approaches for melanoma, including optimal sequencing strategies and agents that target MRD, thereby ultimately improving clinical outcomes for patients.
Insights
This review explores melanoma treatment response phases to targeted therapies (TT) and immune checkpoint inhibitors (ICI). Understanding these phases, especially minimal residual disease (MRD), is key to improving durable responses and patient outcomes.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Cutaneous melanoma presents high mortality in specific populations.
- Targeted therapies (TT) and immune checkpoint inhibitors (ICI) have transformed metastatic melanoma treatment.
- TT offer high initial response but are limited by resistance, while ICI provide durable responses but have lower initial rates.
Purpose of the Study:
- To propose a new framework for understanding melanoma therapeutic response.
- To explore the biological mechanisms of TT and ICI in melanoma.
- To identify optimal sequencing strategies for TT and ICI and agents targeting minimal residual disease (MRD).
Main Methods:
- Review of current literature on TT and ICI in melanoma.
- Analysis of melanoma response in three phases: early response, minimal residual disease (MRD), and disease progression.
- Focus on the tumor immune microenvironment and MRD's role in acquired resistance.
Main Results:
- Melanoma exhibits distinct response phases to TT and ICI: early response, MRD, and progression.
- MRD is identified as a critical phase potentially leading to acquired resistance.
- The interplay between TT, ICI, and the tumor microenvironment is explored across these phases.
Conclusions:
- A novel framework for understanding melanoma therapeutic response is presented.
- This framework may guide the development of novel therapeutic strategies, including optimal sequencing of TT and ICI.
- Targeting MRD is proposed as a key strategy to improve durable responses and clinical outcomes in melanoma patients.
