Current therapeutic management of advanced melanoma patients largely depends on their BRAF mutation status. However, the vast heterogeneity of the tumors hampers the success of therapies targeting the MAPK/ERK pathway alone. Dissecting this heterogeneity will contribute to identifying key players in the oncogenic progression to tailor more effective therapies. We performed a comprehensive molecular and phenotypic characterization of a panel of patient-derived BRAFV600E-positive melanoma cell lines. Transcriptional profiling was used to identify groups of coregulated genes whose expression relates to an increased migratory potential and a higher resistance. A decrease in sensitivity to MAPK/ERK pathway inhibition with vemurafenib or trametinib corresponded with an increasing quiescence and migratory properties of the cells. This was accompanied by the loss of transcriptional signatures of melanocytic differentiation, and the gain of stem cell features that conferred highly-resistant/mesenchymal-like cells with increased xenobiotic efflux capacity. Nevertheless, targeting of the implicated ABC transporters did not improve the response to vemurafenib, indicating that incomplete BRAF inhibition due to reduced drug uptake is not a main driver of resistance. Rather, indifference to MAPK/ERK pathway inhibition arose from the activation of compensatory signaling cascades. The PI3K/AKT pathway in particular showed a higher activity in mesenchymal-like cells, conferring a lower dependency on MAPK/ERK signaling and supporting stem-like properties that could be reverted by dual PI3K/mTOR inhibition with dactolisib. In case of MAPK/ERK independency, therapeutic focus may be shifted to the PI3K/AKT pathway to overcome late-stage resistance in melanoma tumors that have acquired a mesenchymal phenotype.

中文翻译：

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PI3K/AKT 信号允许 MAPK/ERK 通路独立介导黑色素瘤的去分化驱动的治疗耐药性

目前晚期黑色素瘤患者的治疗管理很大程度上取决于他们的 BRAF 突变状态。然而，肿瘤的巨大异质性阻碍了仅针对 MAPK/ERK 通路的治疗的成功。剖析这种异质性将有助于确定致癌进展中的关键参与者，以定制更有效的疗法。我们对一组患者来源的 BRAFV600E 阳性黑色素瘤细胞系进行了全面的分子和表型表征。转录分析被用来识别其表达与增加的迁移潜力和更高的抵抗力相关的共调节基因组。使用 vemurafenib 或 trametinib 对 MAPK/ERK 通路抑制的敏感性降低与细胞静止和迁移特性的增加相对应。这伴随着黑素细胞分化的转录特征的丢失，以及赋予高抗性/间充质样细胞具有增加的外源性外排能力的干细胞特征的获得。然而，针对相关的 ABC 转运蛋白并没有改善对 vemurafenib 的反应，表明由于药物摄取减少导致的不完全 BRAF 抑制不是耐药的主要驱动因素。相反，对 MAPK/ERK 通路抑制的冷漠源于补偿性信号级联的激活。特别是 PI3K/AKT 通路在间充质样细胞中表现出更高的活性，从而降低了对 MAPK/ERK 信号的依赖性，并支持干细胞样特性，这些特性可以通过 dactolisib 的双重 PI3K/mTOR 抑制来恢复。在 MAPK/ERK 独立的情况下，