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Published on: July 8, 2020
The BRAF(V600E) inhibitor, PLX4032, increases type I collagen synthesis in melanoma cells
Molly H Jenkins1, Walburga Croteau2, David W Mullins2
1Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, United States; Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, United States.
Abstract:
Vertical growth phase (VGP) melanoma is frequently metastatic, a process mediated by changes in gene expression, which are directed by signal transduction pathways in the tumor cells. A prominent signaling pathway is the Ras-Raf-Mek-Erk MAPK pathway, which increases expression of genes that promote melanoma progression. Many melanomas harbor a mutation in this pathway, BRAF(V600E), which constitutively activates MAPK signaling and expression of downstream target genes that facilitate tumor progression. In BRAF(V600E) melanoma, the small molecule inhibitor, vemurafenib (PLX4032), has revolutionized therapy for melanoma by inducing rapid tumor regression. This compound down-regulates the expression of many genes. However, in this study, we document that blocking the Ras-Raf-Mek-Erk MAPK pathway, either with an ERK (PLX4032) or a MEK (U1026) signaling inhibitor, in BRAF(V600E) human and murine melanoma cell lines increases collagen synthesis in vitro and collagen deposition in vivo. Since TGFß signaling is a major mediator of collagen synthesis, we examined whether blocking TGFß signaling with a small molecule inhibitor would block this increase in collagen. However, there was minimal reduction in collagen synthesis in response to blocking TGFß signaling, suggesting additional mechanism(s), which may include activation of the p38 MAPK pathway. Presently, it is unclear whether this increased collagen synthesis and deposition in melanomas represent a therapeutic benefit or an unwanted "off target" effect of inhibiting the Ras-Raf-Erk-Mek pathway.
Insights
Targeting the Ras-Raf-Mek-Erk MAPK pathway in BRAF(V600E) melanoma with inhibitors increases collagen synthesis and deposition. This unexpected effect may involve p38 MAPK activation, with unclear therapeutic implications.
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- Vertical growth phase (VGP) melanoma is highly metastatic, driven by altered gene expression via signal transduction pathways.
- The Ras-Raf-Mek-Erk MAPK pathway is crucial for melanoma progression, often activated by BRAF(V600E) mutations.
- Vemurafenib (PLX4032) targets this pathway, revolutionizing melanoma therapy by inducing tumor regression.
Purpose of the Study:
- To investigate the effects of inhibiting the Ras-Raf-Mek-Erk MAPK pathway on collagen synthesis in BRAF(V600E) melanoma.
- To explore potential mechanisms, including TGF-beta and p38 MAPK pathways, underlying observed changes in collagen.
- To determine if increased collagen is a beneficial or detrimental off-target effect of MAPK pathway inhibition.
Main Methods:
- Utilized BRAF(V600E) human and murine melanoma cell lines.
- Administered ERK (PLX4032) and MEK (U1026) signaling inhibitors.
- Assessed collagen synthesis in vitro and deposition in vivo.
- Investigated TGF-beta signaling inhibition and p38 MAPK pathway activation.
Main Results:
- Inhibition of the Ras-Raf-Mek-Erk MAPK pathway significantly increased collagen synthesis in vitro and deposition in vivo.
- Blocking TGF-beta signaling had minimal impact on this increased collagen production.
- Evidence suggests potential involvement of the p38 MAPK pathway in mediating this effect.
Conclusions:
- MAPK pathway inhibition in BRAF(V600E) melanoma leads to increased collagen synthesis and deposition.
- The precise mechanisms, potentially involving p38 MAPK, require further elucidation.
- The clinical significance of this collagen modulation as a therapeutic benefit or off-target effect remains uncertain.
