Mitogen-activated protein kinase dependency in BRAF/RAS wild-type melanoma: A rationale for combination inhibitors
Zizhen Ming1,2, Su Yin Lim1,2, Richard F Kefford2,3
1Department of Biomedical Science, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.
Abstract:
Inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway and immune checkpoint molecules have dramatically improved the survival of patients with BRAFV600 -mutant melanoma. For BRAF/RAS wild-type (WT) melanoma patients, however, immune checkpoint inhibitors remain the only effective therapeutic option with 40% of patients responding to PD-1 inhibition. In the present study, a large panel of 10 BRAFV600 -mutant and 13 BRAF/RAS WT melanoma cell lines was analyzed to examine MAPK dependency and explore the potential utility of MAPK inhibitors in this melanoma subtype. We now show that the majority of BRAF/RAS WT melanoma cell lines (8/13) display some degree of sensitivity to trametinib treatment and resistance to trametinib in this melanoma subtype is associated with, but not mediated by NF1 suppression. Although knockdown of NF1 stimulates RAS and CRAF activity, the activation of CRAF by NF1 knockdown is limited by ERK-dependent feedback in BRAF-mutant cells, but not in BRAF/RAS WT melanoma cells. Thus, NF1 is not a dominant regulator of MAPK signaling in BRAF/RAS WT melanoma, and co-targeting multiple MAP kinase nodes provides a therapeutic opportunity for this melanoma subtype.
Insights
Mitogen-activated protein kinase (MAPK) inhibitors show promise for BRAF/RAS wild-type melanoma. While NF1 suppression is linked to resistance, co-targeting MAPK nodes offers a therapeutic strategy for this subtype.
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- Targeted therapies like MAPK inhibitors and immune checkpoint inhibitors have improved outcomes for BRAF-mutant melanoma.
- BRAF/RAS wild-type (WT) melanoma patients have limited options, primarily relying on immune checkpoint inhibitors with moderate response rates.
Purpose of the Study:
- To investigate the dependency on the MAPK pathway in BRAF/RAS WT melanoma.
- To explore the efficacy of MAPK inhibitors, specifically trametinib, in BRAF/RAS WT melanoma cell lines.
- To understand the role of NF1 suppression in trametinib resistance.
Main Methods:
- Analysis of a panel of 10 BRAF-mutant and 13 BRAF/RAS WT melanoma cell lines.
- Assessment of sensitivity to trametinib treatment.
- Investigation of NF1 suppression and its impact on MAPK signaling components (RAS, CRAF, ERK).
Main Results:
- A majority of BRAF/RAS WT melanoma cell lines (8/13) exhibited sensitivity to trametinib.
- Trametinib resistance was associated with, but not directly caused by, NF1 suppression.
- NF1 knockdown activated RAS and CRAF, but this was counteracted by ERK-dependent feedback in BRAF-mutant cells, unlike in BRAF/RAS WT cells.
Conclusions:
- NF1 is not a primary regulator of MAPK signaling in BRAF/RAS WT melanoma.
- Co-targeting multiple nodes within the MAPK pathway presents a potential therapeutic strategy for BRAF/RAS WT melanoma.
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