Abstract
BRAF is the most common gene mutated in malignant melanoma, and predominately it is a missense mutation of codon 600 in the kinase domain. This oncogenic BRAF missense mutation results in constitutive activation of the mitogen-activate protein kinase (MAPK) pro-survival pathway. Several BRAF inhibitors (BRAFi) have been developed to specifically inhibit BRAFV600 mutations that improve melanoma survival, but resistance and secondary cancer often occur. Causal mechanisms of BRAFi-induced secondary cancer and resistance have been identified through upregulation of MAPK and alternate pro-survival pathways. In addition, overriding of cellular senescence is observed throughout the progression of disease from benign nevi to malignant melanoma. In this review, we discuss melanoma BRAF mutations, the genetic mechanism of BRAFi resistance, and the evidence supporting the role of senescent cells in melanoma disease progression, drug resistance and secondary cancer. We further highlight the potential benefit of targeting senescent cells with senotherapeutics as adjuvant therapy in combating melanoma.
| Original language | English (US) |
|---|---|
| Article number | 2241 |
| Journal | Cancers |
| Volume | 13 |
| Issue number | 9 |
| DOIs | |
| State | Published - May 1 2021 |
Bibliographical note
Funding Information:Author Contributions: The review was conceived by E.L.T. and L.J.N. and the first draft was written by E.L.T. and J.J.H., which was subsequently edited by L.J.N. All authors have read and agreed to the Funding: E.L.T. was funded by the Children’s Cancer Research Fund Emerging Scientist Award
Funding Information:
E.L.T. was funded by the Children’s Cancer Research Fund Emerging Scientist Award and by NIA Postdoctoral Training Grant T32 AG029796. L.J.N. was funded by U01 ES029603.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Keywords
- BRAF inhibitors
- BRAF mutation
- Melanoma
- Resistance
- Secondary cancer
- Senescence
- Senotherapeutics
