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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Paradoxical Role for Wild-Type p53 in Driving Therapy Resistance in Melanoma
Marie R Webster1, Mitchell E Fane2, Gretchen M Alicea3
1Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, 19104, U.S.A.; Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
Abstract:
Metastatic melanoma is an aggressive disease, despite recent improvements in therapy. Eradicating all melanoma cells even in drug-sensitive tumors is unsuccessful in patients because a subset of cells can transition to a slow-cycling state, rendering them resistant to most targeted therapy. It is still unclear what pathways define these subpopulations and promote this resistant phenotype. In the current study, we show that Wnt5A, a non-canonical Wnt ligand that drives a metastatic, therapy-resistant phenotype, stabilizes the half-life of p53 and uses p53 to initiate a slow-cycling state following stress (DNA damage, targeted therapy, and aging). Inhibiting p53 blocks the slow-cycling phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. In vivo, this can be accomplished with a single dose of p53 inhibitor at the commencement of BRAF/MEK inhibitor therapy. These data suggest that taking the paradoxical approach of inhibiting rather than activating wild-type p53 may sensitize previously resistant metastatic melanoma cells to therapy.
Insights
Targeting p53, a tumor suppressor, can overcome therapy resistance in metastatic melanoma. Inhibiting p53 halts slow-cycling cells and sensitizes them to BRAF/MEK inhibitors, improving treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Metastatic melanoma remains aggressive despite advances in targeted therapy.
- Therapy resistance in melanoma is often driven by a subpopulation of slow-cycling cells.
- The specific pathways promoting this resistant phenotype are not fully understood.
Purpose of the Study:
- To investigate the role of Wnt5A and p53 in the development of therapy resistance in metastatic melanoma.
- To determine if inhibiting p53 can sensitize melanoma cells to BRAF/MEK inhibitors.
Main Methods:
- The study analyzed the interaction between Wnt5A and p53 in melanoma cells.
- Experiments involved inducing stress (DNA damage, targeted therapy, aging) to observe cell cycling.
- In vivo studies utilized p53 inhibitors in combination with BRAF/MEK inhibitors.
Main Results:
- Wnt5A was found to stabilize p53, promoting a slow-cycling, therapy-resistant state.
- Inhibition of p53 effectively blocked the slow-cycling phenotype.
- Combining p53 inhibition with BRAF/MEK inhibitors sensitized melanoma cells to therapy in vitro and in vivo.
Conclusions:
- Wild-type p53 plays a critical role in establishing therapy resistance in metastatic melanoma.
- Paradoxically inhibiting p53, rather than activating it, can resensitize resistant melanoma cells to targeted therapies like BRAF/MEK inhibitors.
- This strategy offers a potential new therapeutic approach for overcoming treatment resistance in metastatic melanoma.
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