Patel Hima, Mishra Rosalin, Yacoub Nour, Alanazi Samar, Kilroy Mary Kate, Garrett Joan T
Department of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA.
College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44264, USA.
Cancers (Basel). 2021 Nov 22;13(22):5863. doi: 10.3390/cancers13225863.
The use of BRAF and MEK inhibitors for patients with BRAF-mutant melanoma is limited as patients relapse on treatment as quickly as 6 months due to acquired resistance. We generated trametinib and dabrafenib resistant melanoma (TDR) cell lines to the MEK and BRAF inhibitors, respectively. TDR cells exhibited increased viability and maintenance of downstream p-ERK and p-Akt as compared to parental cells. Receptor tyrosine kinase arrays revealed an increase in p-IGF1R and p-IR in the drug resistant cells versus drug sensitive cells. RNA-sequencing analysis identified IGF1R and INSR upregulated in resistant cell lines compared to parental cells. Analysis of TCGA PanCancer Atlas (skin cutaneous melanoma) showed that patients with a BRAF mutation and high levels of IGF1R and INSR had a worse overall survival. BMS-754807, an IGF1R/IR inhibitor, suppressed cell proliferation along with inhibition of intracellular p-Akt in TDR cells. Dual inhibition of IGF1R and INSR using siRNA reduced cell proliferation. The combination of dabrafenib, trametinib, and BMS-754807 treatment reduced in vivo xenograft tumor growth. Examining the role of IGF1R and IR in mediating resistance to BRAF and MEK inhibitors will expand possible treatment options to aid in long-term success for BRAF-mutant melanoma patients.
由于获得性耐药，BRAF和MEK抑制剂用于BRAF突变型黑色素瘤患者的治疗效果有限，患者在治疗后6个月就会迅速复发。我们分别构建了对MEK抑制剂曲美替尼和BRAF抑制剂达拉非尼耐药的黑色素瘤（TDR）细胞系。与亲代细胞相比，TDR细胞的活力增加，下游p-ERK和p-Akt得以维持。受体酪氨酸激酶阵列显示，耐药细胞中p-IGF1R和p-IR相较于药物敏感细胞有所增加。RNA测序分析表明，与亲代细胞相比，耐药细胞系中IGF1R和INSR上调。对TCGA泛癌图谱（皮肤黑色素瘤）的分析显示，BRAF突变且IGF1R和INSR水平高的患者总生存期较差。IGF1R/IR抑制剂BMS-754807抑制了TDR细胞的增殖，并抑制了细胞内p-Akt。使用siRNA对IGF1R和INSR进行双重抑制可降低细胞增殖。达拉非尼、曲美替尼和BMS-754807联合治疗可减少体内异种移植肿瘤的生长。研究IGF1R和IR在介导对BRAF和MEK抑制剂耐药中的作用，将为BRAF突变型黑色素瘤患者的长期成功治疗拓展可能的治疗选择。
