The therapeutic potential of targeting minimal residual disease in melanoma
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 chec...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-03-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.1197 |
| _version_ | 1797856406544580608 |
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| author | Riyaben P Patel Pretashini M Somasundram Lorey K. Smith Karen E. Sheppard Grant A. McArthur |
| author_facet | Riyaben P Patel Pretashini M Somasundram Lorey K. Smith Karen E. Sheppard Grant A. McArthur |
| author_sort | Riyaben P Patel |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T20:41:02Z |
| format | Article |
| id | doaj.art-42e4ac8011584beba3a1c37d0686c779 |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-04-09T20:41:02Z |
| publishDate | 2023-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj.art-42e4ac8011584beba3a1c37d0686c7792023-03-30T04:20:32ZengWileyClinical and Translational Medicine2001-13262023-03-01133n/an/a10.1002/ctm2.1197The therapeutic potential of targeting minimal residual disease in melanomaRiyaben P Patel0Pretashini M Somasundram1Lorey K. Smith2Karen E. Sheppard3Grant A. McArthur4Cancer Research Division Peter MacCallum Cancer Centre Melbourne Victoria AustraliaFaculty of Medicine Dentistry and Health Sciences, University of Melbourne Parkville Victoria AustraliaCancer Research Division Peter MacCallum Cancer Centre Melbourne Victoria AustraliaCancer Research Division Peter MacCallum Cancer Centre Melbourne Victoria AustraliaCancer Research Division Peter MacCallum Cancer Centre Melbourne Victoria AustraliaAbstract 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.https://doi.org/10.1002/ctm2.1197acquired resistanceBRAF/MEK inhibitorscombination treatmentcross‐resistanceimmune checkpoint inhibitorsintrinsic resistance |
| spellingShingle | Riyaben P Patel Pretashini M Somasundram Lorey K. Smith Karen E. Sheppard Grant A. McArthur The therapeutic potential of targeting minimal residual disease in melanoma Clinical and Translational Medicine acquired resistance BRAF/MEK inhibitors combination treatment cross‐resistance immune checkpoint inhibitors intrinsic resistance |
| title | The therapeutic potential of targeting minimal residual disease in melanoma |
| title_full | The therapeutic potential of targeting minimal residual disease in melanoma |
| title_fullStr | The therapeutic potential of targeting minimal residual disease in melanoma |
| title_full_unstemmed | The therapeutic potential of targeting minimal residual disease in melanoma |
| title_short | The therapeutic potential of targeting minimal residual disease in melanoma |
| title_sort | therapeutic potential of targeting minimal residual disease in melanoma |
| topic | acquired resistance BRAF/MEK inhibitors combination treatment cross‐resistance immune checkpoint inhibitors intrinsic resistance |
| url | https://doi.org/10.1002/ctm2.1197 |
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