The Role of Senescent Cells in Acquired Drug Resistance and Secondary Cancer in BRAFi-Treated Melanoma.
The Role of Senescent Cells in Acquired Drug Resistance and Secondary Cancer in BRAFi-Treated Melanoma.
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DOI：
10.3390/cancers13092241
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发表时间：
2021-05-07
期刊：
影响因子：
5.2
通讯作者：
Niedernhofer LJ
中科院分区：
文献类型：
--
作者：
Thompson EL;Hu JJ;Niedernhofer LJ
黑色素瘤治疗的进展包括针对恶性黑色素瘤中发现的主要致癌突变的v-Raf鼠肉瘤病毒致癌基因同源物B（BRAF）抑制剂。尽管BRAF抑制剂（BRAFi）疗法取得了初步成功，但仍经常发生耐药性和继发性癌症。耐药性和继发性癌症的机制依赖于绕过衰老的促存活途径的上调。在整个黑色素瘤进展过程中反复鉴定细胞衰老表型证明了衰老细胞在抗性和继发性癌症发展中的作用。在黑色素瘤治疗中使用senotherapeutics可能为潜在改善临床结局提供新方法。BRAF是恶性黑色素瘤中最常见的突变基因，主要是激酶结构域中密码子600的错义突变。这种致癌的BRAF错义突变导致有丝分裂原激活蛋白激酶（MAPK）促生存途径的组成性激活。已经开发了几种BRAF抑制剂（BRAFi）来特异性抑制BRAFV 600突变，这些突变改善了黑色素瘤存活率，但经常发生耐药性和继发性癌症。BRAFi诱导的继发性癌症和耐药性的原因机制已通过MAPK和替代促存活途径的上调来确定。此外，在从良性痣到恶性黑色素瘤的整个疾病进展过程中观察到细胞衰老的覆盖。在这篇综述中，我们讨论了黑色素瘤BRAF突变，BRAFi耐药的遗传机制，以及支持衰老细胞在黑色素瘤疾病进展，耐药性和继发性癌症中作用的证据。我们进一步强调了用senotherapeutics靶向衰老细胞作为对抗黑色素瘤的辅助疗法的潜在益处。
Advances in melanoma treatment include v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors that target the predominant oncogenic mutation found in malignant melanoma. Despite initial success of the BRAF inhibitor (BRAFi) therapies, resistance and secondary cancer often occur. Mechanisms of resistance and secondary cancer rely on upregulation of pro-survival pathways that circumvent senescence. The repeated identification of a cellular senescent phenotype throughout melanoma progression demonstrates the contribution of senescent cells in resistance and secondary cancer development. Incorporating senotherapeutics in melanoma treatment may offer a novel approach for potentially improving clinical outcome. 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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影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
DOI：
10.1038/modpathol.2017.104
发表时间：
2018-01
期刊：
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
影响因子：
--
作者：
Cheng L;Lopez-Beltran A;Massari F;MacLennan GT;Montironi R
通讯作者：
Montironi R
影响因子：
28.2
作者：
Abdel-Wahab O;Klimek VM;Gaskell AA;Viale A;Cheng D;Kim E;Rampal R;Bluth M;Harding JJ;Callahan MK;Merghoub T;Berger MF;Solit DB;Rosen N;Levine RL;Chapman PB
通讯作者：
Chapman PB
影响因子：
10.3
作者：
Anforth, R. M.;Blumetti, T. C. M. P.;Fernandez-Penas, P.
通讯作者：
Fernandez-Penas, P.
影响因子：
3.3
作者：
Ashida, Atsuko;Sakaizawa, Kaori;Okuyama, Ryuhei
通讯作者：
Okuyama, Ryuhei