Changes in the Transcriptome and Chromatin Landscape in BRAFi-Resistant Melanoma Cells.

Changes in the Transcriptome and Chromatin Landscape in BRAFi-Resistant Melanoma Cells.

Metastatic and drug-resistant melanoma are leading causes of skin cancer–associated death. Mitogen-associated protein kinase (MAPK) pathway inhibitors and immunotherapies have provided substantial benefits to patients with melanoma. However, long-term therapeutic efficacy has been limited due to emergence of treatment resistance. Despite the identification of several molecular mechanisms underlying the development of resistant phenotypes, significant progress has still not been made toward the effective treatment of drug-resistant melanoma. Therefore, the identification of new targets and mechanisms driving drug resistance in melanoma represents an unmet medical need. In this study, we performed unbiased RNA-sequencing (RNA-seq) and assay for transposase-accessible chromatin with sequencing (ATAC-seq) to identify new targets and mechanisms that drive resistance to MAPK pathway inhibitors targeting BRAF and MAPK kinase (MEK) in BRAF-mutant melanoma cells. An integrative analysis of ATAC-seq combined with RNA-seq showed that global changes in chromatin accessibility affected the mRNA expression levels of several known and novel genes, which consequently modulated multiple oncogenic signaling pathways to promote resistance to MAPK pathway inhibitors in melanoma cells. Many of these genes were also associated with prognosis predictions in melanoma patients. This study resulted in the identification of new genes and signaling pathways that might be targeted to treat MEK or BRAF inhibitors resistant melanoma patients. The present study applied new and advanced approaches to identify unique changes in chromatin accessibility regions that modulate gene expression associated with pathways to promote the development of resistance to MAPK pathway inhibitors.

转移性和耐药性黑色素瘤是皮肤癌相关死亡的主要原因。丝裂原相关蛋白激酶（MAPK）通路抑制剂和免疫疗法为黑色素瘤患者带来了显著益处。然而，由于治疗耐药性的出现，长期治疗效果受到限制。尽管已经确定了耐药表型发展的几种分子机制，但在耐药性黑色素瘤的有效治疗方面仍未取得重大进展。因此，确定驱动黑色素瘤耐药的新靶点和机制是一项尚未满足的医疗需求。在本研究中，我们进行了无偏倚的RNA测序（RNA - seq）以及转座酶可及染色质测序分析（ATAC - seq），以确定在BRAF突变的黑色素瘤细胞中驱动对靶向BRAF和MAPK激酶（MEK）的MAPK通路抑制剂产生耐药性的新靶点和机制。对ATAC - seq与RNA - seq的综合分析表明，染色质可及性的全局变化影响了几个已知和新基因的mRNA表达水平，从而调节了多个致癌信号通路，促进了黑色素瘤细胞对MAPK通路抑制剂的耐药性。这些基因中的许多也与黑色素瘤患者的预后预测相关。这项研究确定了可能作为治疗对MEK或BRAF抑制剂耐药的黑色素瘤患者靶点的新基因和信号通路。本研究应用了新的先进方法来确定染色质可及性区域的独特变化，这些变化调节与促进MAPK通路抑制剂耐药性发展的通路相关的基因表达。