Treatment of advanced BRAF^V600-mutant melanoma using a BRAF inhibitor or its combination with a MEK inhibitor typically elicits partial responses. We compared the transcriptomes of patient-derived tumors regressing on MAPK inhibitor (MAPKi) therapy against MAPKi-induced temporal transcriptomic states in human melanoma cell lines or murine melanoma in immune-competent mice. Despite heterogeneous dynamics of clinical tumor regression, residual tumors displayed highly recurrent transcriptomic alterations and enriched processes, which were also observed in MAPKi-selected cell lines (implying tumor cell–intrinsic reprogramming) or in bulk mouse tumors (and the CD45-negative or CD45-positive fractions, implying tumor cell–intrinsic or stromal/immune alterations, respectively). Tumor cell–intrinsic reprogramming attenuated MAPK dependency, while enhancing mesenchymal, angiogenic, and IFN-inflammatory features and growth/survival dependence on multi-RTKs and PD-L2. In the immune compartment, PD-L2 upregulation in CD11c⁺ immunocytes drove the loss of T-cell inflammation and promoted BRAFi resistance. Thus, residual melanoma early on MAPKi therapy already displays potentially exploitable adaptive transcriptomic, epigenomic, immune-regulomic alterations.

SIGNIFICANCE: Incomplete MAPKi-induced melanoma regression results in transcriptome/methylome-wide reprogramming and MAPK-redundant escape. Although regressing/residual melanoma is highly T cell–inflamed, stromal adaptations, many of which are tumor cell–driven, could suppress/eliminate intratumoral T cells, reversing tumor regression. This catalog of recurrent alterations helps identify adaptations such as PD-L2 operative tumor cell intrinsically and/or extrinsically early on therapy.Cancer Discov; 7(11); 1–18. ©2017 AACR.

See related commentary by Haq, p. 1216.

先进BRAF ^{V600的处理}使用BRAF抑制剂或其与MEK抑制剂联合使用的突变型黑色素瘤通常会引起部分反应。我们比较了抗MAPKi诱导的人黑色素瘤细胞系或小鼠黑色素瘤在免疫功能小鼠中的时间转录组状态的MAPK抑制剂（MAPKi）治疗后回归的患者源性肿瘤的转录组。尽管临床肿瘤消退的动力学存在异质性，但残留肿瘤仍显示出高度复发的转录组改变和富集过程，在MAPKi选择的细胞系（暗示肿瘤细胞内在重编程）或大量小鼠肿瘤（以及CD45阴性或CD45）中也观察到了这种现象。阳性部分，分别暗示肿瘤细胞内在或基质/免疫改变。肿瘤细胞内在重编程减弱了MAPK依赖性，同时增强了间充质，血管生成，以及多种RTK和PD-L2对IFN的炎症反应以及生长/生存的依赖性。在免疫区中，CD11c中的PD-L2上调⁺免疫细胞带动了T细胞炎症的丧失，并增强了BRAFi抵抗力。因此，MAPKi治疗早期的残留黑色素瘤已经显示出潜在的可利用的适应性转录组学，表观基因组学，免疫调节学改变。

重要性：不完全的MAPKi诱导的黑色素瘤消退导致转录组/甲基组范围的重编程和MAPK冗余逃逸。尽管消退性/残留性黑色素瘤是高度T细胞炎症的，但基质适应（其中许多是肿瘤细胞驱动的）可以抑制/消除肿瘤内T细胞，从而逆转肿瘤消退。这种复发性改变的目录有助于在治疗早期从内在和/或外在地识别适应性疾病，例如PD-L2手术性肿瘤细胞。巨蟹座Discov; 7（11）；1–18。©2017 AACR。

参见Haq的相关评论，第1页。1216。