Target therapies based on BRAF and MEK inhibitors (MAPKi) have changed the therapeutic landscape for metastatic melanoma patients bearing mutations in the BRAF kinase. However, the emergence of drug resistance imposes the necessity to conceive novel therapeutic strategies capable to achieve a more durable disease control. In the last years, retrotransposons laying in human genome have been shown to undergo activation during tumorigenesis, where they contribute to genomic instability. Their activation can be efficiently controlled with reverse transcriptase inhibitors (RTIs) frequently used in the treatment of AIDS. These drugs have demonstrated anti-proliferative effects in several cancer models, including also metastatic melanoma. However, to our knowledge no previous study investigated the capability of RTIs to mitigate drug resistance to target therapy in BRAF-mutant melanomas. In this short report we show that the non-nucleoside RTI, SPV122 in combination with MAPKi strongly inhibits BRAF-mutant melanoma cell growth, induces apoptosis, and delays the emergence of resistance to target therapy in vitro. Mechanistically, this combination strongly induces DNA double-strand breaks, mitochondrial membrane depolarization and increased ROS levels. Our results shed further light on the molecular activity of RTI in melanoma and pave the way to their use as a novel therapeutic option to improve the efficacy of target therapy.

中文翻译：

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逆转录酶抑制可增强 BRAF 突变黑色素瘤的靶向治疗：对细胞增殖、凋亡、DNA 损伤、ROS 诱导和线粒体膜去极化的影响。

基于 BRAF 和 MEK 抑制剂 (MAPKi) 的靶向疗法改变了携带 BRAF 激酶突变的转移性黑色素瘤患者的治疗前景。然而，耐药性的出现使得必须构思能够实现更持久的疾病控制的新型治疗策略。在过去的几年中，人类基因组中的逆转录转座子已被证明在肿瘤发生过程中会被激活，从而导致基因组不稳定。它们的激活可以通过经常用于治疗艾滋病的逆转录酶抑制剂 (RTI) 来有效控制。这些药物已在多种癌症模型中显示出抗增殖作用，包括转移性黑色素瘤。然而，据我们所知，以前没有研究调查过 RTIs 减轻 BRAF 突变黑色素瘤靶向治疗耐药性的能力。在这份简短的报告中，我们展示了非核苷 RTI、SPV122 与 MAPKi 的组合强烈抑制 BRAF 突变黑色素瘤细胞的生长，诱导细胞凋亡，并延迟了体外靶向治疗耐药性的出现。从机制上讲，这种组合强烈诱导 DNA 双链断裂、线粒体膜去极化和增加 ROS 水平。我们的结果进一步阐明了 RTI 在黑色素瘤中的分子活性，并为将其用作提高靶向治疗功效的新型治疗选择铺平了道路。SPV122 与 MAPKi 结合强烈抑制 BRAF 突变黑色素瘤细胞的生长，诱导细胞凋亡，并延迟体外靶向治疗耐药性的出现。从机制上讲，这种组合强烈诱导 DNA 双链断裂、线粒体膜去极化和增加 ROS 水平。我们的结果进一步阐明了 RTI 在黑色素瘤中的分子活性，并为将其用作提高靶向治疗功效的新型治疗选择铺平了道路。SPV122 与 MAPKi 结合强烈抑制 BRAF 突变黑色素瘤细胞的生长，诱导细胞凋亡，并延迟体外靶向治疗耐药性的出现。从机制上讲，这种组合强烈诱导 DNA 双链断裂、线粒体膜去极化和增加 ROS 水平。我们的结果进一步阐明了 RTI 在黑色素瘤中的分子活性，并为将其用作提高靶向治疗功效的新型治疗选择铺平了道路。