The development of BRAF and MEK inhibitors (BRAFi/MEKi) has led to major advances in melanoma treatment. However, the emergence of resistance mechanisms limits the benefit duration and a complete response occurs in less than 20% of patients receiving BRAFi ± MEKi. In this study, we evaluated the impact of an intermittent versus continuous dosing schedule of BRAF/MEK inhibition in a melanoma model mildly sensitive to a BRAF inhibitor. The combination of a BRAFi with three different MEKi was studied with a continuous or intermittent dosing schedule in vivo, in a xenografted melanoma model and ex vivo using histoculture drug response assays (HDRAs) of patient-derived xenografts (PDX). To further understand the underlying molecular mechanisms of therapeutic efficacy, a biomarker pharmacodynamic readout was evaluated.

An equal impact on tumor growth was observed in monotherapy or bitherapy regimens whether we used continuous and intermittent dosing schedules, with no significant differences in biomarkers expression between the treatments. The antitumoral effect was mostly due to modulations of expression of cell cycle and apoptotic mediators. Moreover, ex vivo studies did not show significant differences between the dosing schedules.

In this context, our preclinical and pharmacodynamic results converged to show the similarity between intermittent and continuous treatments with either BRAFi or MEKi alone or with the combination of both.

BRAF 和 MEK 抑制剂 (BRAFi/MEKi) 的开发导致黑色素瘤治疗取得重大进展。然而，耐药机制的出现限制了获益持续时间，并且只有不到 20% 的接受 BRAFi ± MEKi 的患者出现完全缓解。在这项研究中，我们评估了对 BRAF 抑制剂轻度敏感的黑色素瘤模型中 BRAF/MEK 抑制的间歇与连续给药方案的影响。 BRAFi 与三种不同 MEKi 的组合在体内、异种移植黑色素瘤模型中以连续或间歇给药方案进行研究，并使用患者来源的异种移植物 (PDX) 的组织培养药物反应测定 (HDRAs) 进行离体研究。为了进一步了解治疗功效的潜在分子机制，对生物标志物药效学读数进行了评估。

无论我们使用连续还是间歇给药方案，在单一疗法或双疗法方案中都观察到对肿瘤生长的相同影响，并且治疗之间的生物标志物表达没有显着差异。抗肿瘤作用主要是由于细胞周期和凋亡介质表达的调节。此外，离体研究并未显示给药方案之间存在显着差异。

在这种情况下，我们的临床前和药效学结果趋于一致，显示单独使用 BRAFi 或 MEKi 或两者组合的间歇性治疗和连续治疗之间的相似性。