Hodgkinson Arran, Trucu Dumitru, Lacroix Matthieu, Le Cam Laurent, Radulescu Ovidiu
Living Systems Institute, University of Exeter, Exeter, United Kingdom.
Division of Mathematics, University of Dundee, Dundee, United Kingdom.
Front Oncol. 2022 Apr 14;12:857572. doi: 10.3389/fonc.2022.857572. eCollection 2022.
Cutaneous melanoma is a highly invasive tumor and, despite the development of recent therapies, most patients with advanced metastatic melanoma have a poor clinical outcome. The most frequent mutations in melanoma affect the BRAF oncogene, a protein kinase of the MAPK signaling pathway. Therapies targeting both BRAF and MEK are effective for only 50% of patients and, almost systematically, generate drug resistance. Genetic and non-genetic mechanisms associated with the strong heterogeneity and plasticity of melanoma cells have been suggested to favor drug resistance but are still poorly understood. Recently, we have introduced a novel mathematical formalism allowing the representation of the relation between tumor heterogeneity and drug resistance and proposed several models for the development of resistance of melanoma treated with BRAF/MEK inhibitors. In this paper, we further investigate this relationship by using a new computational model that copes with multiple cell states identified by single cell mRNA sequencing data in melanoma treated with BRAF/MEK inhibitors. We use this model to predict the outcome of different therapeutic strategies. The reference therapy, referred to as "continuous" consists in applying one or several drugs without disruption. In "combination therapy", several drugs are used sequentially. In "adaptive therapy" drug application is interrupted when the tumor size is below a lower threshold and resumed when the size goes over an upper threshold. We show that, counter-intuitively, the optimal protocol in combination therapy of BRAF/MEK inhibitors with a hypothetical drug targeting cell states that develop later during the tumor response to kinase inhibitors, is to treat first with this hypothetical drug. Also, even though there is little difference in the timing of emergence of the resistance between continuous and adaptive therapies, the spatial distribution of the different melanoma subpopulations is more zonated in the case of adaptive therapy.
皮肤黑色素瘤是一种高度侵袭性肿瘤，尽管近年来治疗方法有所发展，但大多数晚期转移性黑色素瘤患者的临床预后仍很差。黑色素瘤中最常见的突变影响BRAF癌基因，它是MAPK信号通路的一种蛋白激酶。针对BRAF和MEK的疗法仅对50%的患者有效，而且几乎不可避免地会产生耐药性。与黑色素瘤细胞的强异质性和可塑性相关的遗传和非遗传机制被认为有利于耐药性，但仍知之甚少。最近，我们引入了一种新的数学形式，用于表示肿瘤异质性与耐药性之间的关系，并提出了几种BRAF/MEK抑制剂治疗黑色素瘤耐药性发展的模型。在本文中，我们通过使用一种新的计算模型进一步研究这种关系，该模型处理BRAF/MEK抑制剂治疗的黑色素瘤单细胞mRNA测序数据所识别的多种细胞状态。我们使用这个模型来预测不同治疗策略的结果。参考疗法，称为“连续疗法”，包括不间断地应用一种或几种药物。在“联合疗法”中，几种药物依次使用。在“适应性疗法”中，当肿瘤大小低于下限阈值时中断药物应用，当大小超过上限阈值时恢复应用。我们发现，与直觉相反，BRAF/MEK抑制剂与一种针对肿瘤对激酶抑制剂反应后期出现的细胞状态的假设药物联合治疗的最佳方案是先用这种假设药物治疗。此外，尽管连续疗法和适应性疗法在耐药性出现的时间上差异不大，但在适应性疗法的情况下，不同黑色素瘤亚群的空间分布更呈带状。
