The role of senescent cells in acquired drug resistance and secondary cancer in brafi-treated melanoma

Elizabeth L Thompson; Jiayi Hu; Laura J. Niedernhofer

doi:10.3390/cancers13092241

The role of senescent cells in acquired drug resistance and secondary cancer in brafi-treated melanoma

Elizabeth L Thompson, Jiayi Hu, Laura J. Niedernhofer

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9 Scopus citations

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 BRAF^V600 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	https://doi.org/10.3390/cancers13092241
State	Published - May 1 2021

Bibliographical note

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.

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

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

BRAF inhibitors
BRAF mutation
Melanoma
Resistance
Secondary cancer
Senescence
Senotherapeutics

PubMed: MeSH publication types

Review
Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/cancers13092241

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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.",

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The role of senescent cells in acquired drug resistance and secondary cancer in brafi-treated melanoma

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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