The therapeutic potential of targeting minimal residual disease in melanoma

Patel, RP; Somasundram, PM; Smith, LK; Sheppard, KE; McArthur, GA

Author(s): Patel, RP; Somasundram, PM; Smith, LK; Sheppard, KE; McArthur, GA;
Details: Publication Year 2023-03,Volume 13,Issue #3,Page e1197
Journal Title: Clinical and Translational Medicine
Publication Type: Review
Abstract: 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.
Publisher: Wiley
Keywords: Humans; *Melanoma/drug therapy/pathology; *Skin Neoplasms/drug therapy/pathology; Neoplasm, Residual/drug therapy; Immunotherapy; Tumor Microenvironment; BRAF/MEK inhibitors; acquired resistance; combination treatment; cross-resistance; immune checkpoint inhibitors; intrinsic resistance; melanoma; minimal residual disease
Department(s): Laboratory Research
PubMed ID: 36967556
Publisher's Version: https://doi.org/10.1002/ctm2.1197
Open Access at Publisher's Site: https://doi.org/10.1002/ctm2.1197
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-07-11 06:23:30

Last Modified: 2023-07-11 06:25:37