Adrenocortical carcinomas (ACCs) overexpress insulin-like growth factor 2 (IGF2), that drives a proliferative autocrine loop by binding to IGF1R and IR, but IGF1R/IR-targeted therapies failed in ACC patients.

The cytoskeleton actin-binding protein filamin A (FLNA) impairs IR signalling in melanoma cells.

Aims of this study were to test FLNA involvement in regulating IGF1R and IR responsiveness to both IGF2 and inhibitors in ACC.

In ACC cells H295R and SW13 and primary cultures (1ACC, 4 adenomas) we found that IGF1R and IR interacted with FLNA, and FLNA silencing increased IGF1R and reduced IR expression, with a downstream effect of increased cell proliferation and ERK phosphorylation.

In addition, FLNA knockdown potentiated antiproliferative effects of IGF1R/IR inhibitor Linsitinib and IGF1R inhibitor NVP-ADW742 in H295R.

Finally, Western blot showed lower FLNA expression in ACCs (n = 10) than in ACAs (n = 10) and an inverse correlation of FLNA/IGF1R ratio with ERK phosphorylation in ACCs only.

In conclusion, we demonstrated that low FLNA levels enhance both IGF2 proliferative effects and IGF1R/IR inhibitors efficacy in ACC cells, suggesting FLNA as a new factor influencing tumor clinical behavior and the response to the therapy with IGF1R/IR-targeted drugs.

肾上腺皮质癌（ACC）过表达胰岛素样生长因子2（IGF2），该因子通过与IGF1R和IR结合而驱动增殖性自分泌环，但以IGF1R / IR为靶点的疗法在ACC患者中失败。

细胞骨架肌动蛋白结合蛋白丝蛋白A（FLNA）损害黑素瘤细胞中的红外信号。

这项研究的目的是测试FLNA参与调节IGF1R和IR对ACC中IGF2和抑制剂的反应。

在ACC细胞H295R和SW13以及原代培养物中（1ACC，4个腺瘤），我们发现IGF1R和IR与FLNA相互作用，而FLNA沉默可增加IGF1R并降低IR表达，并具有增加细胞增殖和ERK磷酸化的下游作用。

此外，FLNA敲低增强了IGF1R / IR抑制剂Linsitinib和IGF1R抑制剂NVP-ADW742在H295R中的抗增殖作用。

最后，蛋白质印迹显示，ACC中的FLNA表达（n = 10）比ACA中的表达低（n = 10），并且FLNA / IGF1R比值与ACC中ERK磷酸化呈负相关。

总之，我们证明了低FLNA水平可增强ACC细胞中IGF2的增殖作用和IGF1R / IR抑制剂的功效，这表明FLNA是影响肿瘤临床行为和以IGF1R / IR靶向药物治疗反应的新因素。