Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in NRAS-Mutant Melanoma Cell Lines.
Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in NRAS-Mutant Melanoma Cell Lines.
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DOI：
10.3390/cancers13092012
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发表时间：
2021-04-22
期刊：
影响因子：
5.2
通讯作者：
Neubig RR
中科院分区：
文献类型：
--
作者：
Appleton KM;Palsuledesai CC;Misek SA;Blake M;Zagorski J;Gallo KA;Dexheimer TS;Neubig RR
恶性黑色素瘤是最具侵袭性的皮肤癌，由于对靶向治疗剂产生耐药性，治疗通常无效。具有突变的BRAF基因的最普遍的黑色素瘤形式具有有效的治疗，但是黑色素瘤中第二常见的突变（NRAS）导致缺乏靶向治疗的肿瘤。在这项研究中，我们表明，NRAS突变的人黑色素瘤细胞是最耐抑制的致癌途径有第二个激活的途径（Rho）。在几个点之一抑制该途径可以产生比单独抑制NRAS途径更有效的细胞杀伤。这增加了这样一种可能性，即这种联合治疗可以证明对那些对现有靶向治疗（如vemurafenib和trametinib）无效的黑色素瘤有效。Ras/MEK/ERK通路一直是黑色素瘤靶向治疗的主要焦点;它在几乎80%的人皮肤黑色素瘤中异常激活（约50%的BRAFV 600突变和约30%的NRAS突变）。虽然靶向MAPK途径的药物在BRAFV 600突变型黑素瘤患者中取得了成功，但此类疗法在NRAS突变型黑素瘤患者中无效，部分原因是其细胞抑制作用和原发性耐药性。在这里，我们证明了增加的Rho/MRTF途径激活与高内在耐药性的MEK抑制剂，曲美替尼，在一组NRAS突变黑色素瘤细胞系。曲美替尼与Rho/MRTF通路抑制剂CCG-222740的组合在体外协同降低NRAS突变黑素瘤细胞系中的细胞活力。此外，CCG-222740与曲美替尼的组合在对曲美替尼高度耐药的SK-Mel-147细胞中诱导细胞凋亡并降低克隆形成。这些发现表明Rho/MRTF途径在NRAS突变型黑色素瘤细胞系亚组中内在曲美替尼耐药性中的作用，并突出了同时靶向Rho/MRTF途径和MEK在NRAS突变型黑色素瘤中的治疗潜力。
Malignant melanoma is the most aggressive skin cancer, and treatment is often ineffective due to the development of resistance to targeted therapeutic agents. The most prevalent form of melanoma with a mutated BRAF gene has an effective treatment, but the second most common mutation in melanoma (NRAS) leads to tumors that lack targeted therapies. In this study, we show that NRAS mutant human melanoma cells that are most resistant to inhibition of the oncogenic pathway have a second activated pathway (Rho). Inhibiting that pathway at one of several points can produce more effective cell killing than inhibition of the NRAS pathway alone. This raises the possibility that such a combination treatment could prove effective in those melanomas that fail to respond to existing targeted therapies such as vemurafenib and trametinib. The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% BRAFV600 mutations and ≈30% NRAS mutations). While drugs targeting the MAPK pathway have yielded success in BRAFV600 mutant melanoma patients, such therapies have been ineffective in patients with NRAS mutant melanomas in part due to their cytostatic effects and primary resistance. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. A combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells, which are highly resistant to trametinib. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlight the therapeutic potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.
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影响因子：
7.3
作者：
Cheeseman MD;Chessum NE;Rye CS;Pasqua AE;Tucker MJ;Wilding B;Evans LE;Lepri S;Richards M;Sharp SY;Ali S;Rowlands M;O'Fee L;Miah A;Hayes A;Henley AT;Powers M;Te Poele R;De Billy E;Pellegrino L;Raynaud F;Burke R;van Montfort RL;Eccles SA;Workman P;Jones K
通讯作者：
Jones K
影响因子：
64.8
作者：
Clark, EA;Golub, TR;Hynes, RO
通讯作者：
Hynes, RO
影响因子：
8.4
作者：
Kirchberger, Michael Constantin;Ugurel, Selma;Heinzerling, Lucie
通讯作者：
Heinzerling, Lucie
影响因子：
--
作者：
Licciulli, Silvia;Luise, Chiara;Alcalay, Myriam
通讯作者：
Alcalay, Myriam
影响因子：
8
作者：
Misek, S. A.;Appleton, K. M.;Neubig, R. R.
通讯作者：
Neubig, R. R.