Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA.
Vanderbilt University, Nashville, Tennessee, USA.
JCI Insight. 2018 Jul 26;3(14). doi: 10.1172/jci.insight.120422.
Resistance to current therapies still impacts a significant number of melanoma patients and can be regulated by epigenetic alterations. Analysis of global cytosine methylation in a cohort of primary melanomas revealed a pattern of early demethylation associated with overexpression of oncogenic transcripts. Loss of methylation and associated overexpression of the CSF 1 receptor (CSF1R) was seen in a majority of tumors and was driven by an alternative, endogenous viral promoter in a subset of samples. CSF1R was particularly elevated in melanomas with BRAF and other MAPK activating mutations. Furthermore, rebound ERK activation after BRAF inhibition was associated with RUNX1-mediated further upregulation of CSF-1R and its ligand IL-34. Importantly, increased CSF-1R and IL-34 overexpression were detected in an independent cohort of resistant melanomas. Inhibition of CSF-1R kinase or decreased CSF-1R expression by RNAi reduced 3-D growth and invasiveness of melanoma cells. Coinhibition of CSF-1R and BRAF resulted in synergistic efficacy in vivo. To our knowledge, our data unveil a previously unknown role for the autocrine-regulated CSF-1R in BRAF V600E resistance and provide a preclinical rationale for targeting this pathway in melanoma.
目前的治疗方法仍然会对许多黑色素瘤患者产生影响，而这种影响可以通过表观遗传改变来调控。对一组原发性黑色素瘤的全基因组胞嘧啶甲基化分析显示，早期去甲基化与致癌转录本的过表达有关。在大多数肿瘤中观察到 CSF1R 的甲基化丢失及其过表达，而在部分样本中，这种丢失是由替代的内源性病毒启动子驱动的。CSF1R 在具有 BRAF 和其他 MAPK 激活突变的黑色素瘤中尤其升高。此外，BRAF 抑制后 ERK 的反弹激活与 RUNX1 介导的 CSF-1R 及其配体 IL-34 的进一步上调有关。重要的是，在独立的耐药性黑色素瘤队列中检测到 CSF-1R 和 IL-34 的过表达增加。CSF-1R 激酶的抑制或 RNAi 降低 CSF-1R 的表达减少了黑色素瘤细胞的 3-D 生长和侵袭性。CSF-1R 和 BRAF 的联合抑制在体内具有协同疗效。据我们所知，我们的数据揭示了 CSF-1R 在内分泌调节中在 BRAF V600E 耐药性中的先前未知作用，并为该途径在黑色素瘤中的靶向治疗提供了临床前依据。
