Sabbatino Francesco, Wang Yangyang, Wang Xinhui, Flaherty Keith T, Yu Ling, Pepin David, Scognamiglio Giosue, Pepe Stefano, Kirkwood John M, Cooper Zachary A, Frederick Dennie T, Wargo Jennifer A, Ferrone Soldano, Ferrone Cristina R
Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA.
Oncotarget. 2014 Apr 15;5(7):1926-41. doi: 10.18632/oncotarget.1878.
Control of BRAF(V600E) metastatic melanoma by BRAF inhibitor (BRAF-I) is limited by intrinsic and acquired resistance. Growth factor receptor up-regulation is among the mechanisms underlying BRAF-I resistance of melanoma cells. Here we demonstrate for the first time that PDGFRα up-regulation causes BRAF-I resistance. PDGFRα inhibition by PDGFRα-specific short hairpin (sh)RNA and by PDGFRα inhibitors restores and increases melanoma cells' sensitivity to BRAF-I in vitro and in vivo. This effect reflects the inhibition of ERK and AKT activation which is associated with BRAF-I resistance of melanoma cells. PDGFRα up-regulation is mediated by Sonic Hedgehog Homolog (Shh) pathway activation which is induced by BRAF-I treatment. Similarly to PDGFRα inhibition, Shh inhibition by LDE225 restores and increases melanoma cells' sensitivity to BRAF-I. These effects are mediated by PDGFRα down-regulation and by ERK and AKT inhibition. The clinical relevance of these data is indicated by the association of PDGFRα up-regulation in melanoma matched biopsies of BRAF-I +/- MEK inhibitor treated patients with shorter time to disease progression and less tumor regression. These findings suggest that monitoring patients for early PDGFRα up-regulation will facilitate the identification of those who may benefit from the treatment with BRAF-I in combination with clinically approved PDGFRα or Shh inhibitors.
BRAF抑制剂（BRAF-I）对BRAF（V600E）转移性黑色素瘤的控制受到内在和获得性耐药的限制。生长因子受体上调是黑色素瘤细胞对BRAF-I耐药的潜在机制之一。在此，我们首次证明PDGFRα上调导致BRAF-I耐药。通过PDGFRα特异性短发夹（sh）RNA和PDGFRα抑制剂抑制PDGFRα可在体外和体内恢复并增加黑色素瘤细胞对BRAF-I的敏感性。这种效应反映了对ERK和AKT激活的抑制，而这与黑色素瘤细胞对BRAF-I的耐药相关。PDGFRα上调由BRAF-I治疗诱导的音猬因子同源物（Shh）信号通路激活介导。与抑制PDGFRα类似，LDE225抑制Shh可恢复并增加黑色素瘤细胞对BRAF-I的敏感性。这些效应由PDGFRα下调以及ERK和AKT抑制介导。BRAF-I±MEK抑制剂治疗患者的黑色素瘤配对活检中PDGFRα上调与疾病进展时间缩短和肿瘤退缩较少相关，这表明了这些数据的临床相关性。这些发现提示，监测患者早期PDGFRα上调将有助于识别那些可能从BRAF-I与临床批准的PDGFRα或Shh抑制剂联合治疗中获益的患者。
