Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.
Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA.
Nat Commun. 2019 Mar 21;10(1):1296. doi: 10.1038/s41467-019-09179-w.
The dysregulation of Fbxo4-cyclin D1 axis occurs at high frequency in esophageal squamous cell carcinoma (ESCC), where it promotes ESCC development and progression. However, defining a therapeutic vulnerability that results from this dysregulation has remained elusive. Here we demonstrate that Rb and mTORC1 contribute to Gln-addiction upon the dysregulation of the Fbxo4-cyclin D1 axis, which leads to the reprogramming of cellular metabolism. This reprogramming is characterized by reduced energy production and increased sensitivity of ESCC cells to combined treatment with CB-839 (glutaminase 1 inhibitor) plus metformin/phenformin. Of additional importance, this combined treatment has potent efficacy in ESCC cells with acquired resistance to CDK4/6 inhibitors in vitro and in xenograft tumors. Our findings reveal a molecular basis for cancer therapy through targeting glutaminolysis and mitochondrial respiration in ESCC with dysregulated Fbxo4-cyclin D1 axis as well as cancers resistant to CDK4/6 inhibitors.
Fbxo4-cyclin D1 轴的失调在食管鳞状细胞癌（ESCC）中高频发生，它促进了 ESCC 的发展和进展。然而，定义由此失调导致的治疗弱点仍然难以捉摸。在这里，我们证明了在 Fbxo4-cyclin D1 轴失调的情况下，Rb 和 mTORC1 有助于 Gln 成瘾，这导致了细胞代谢的重编程。这种重编程的特征是能量产生减少，以及 ESCC 细胞对 CB-839（谷氨酰胺酶 1 抑制剂）联合二甲双胍/苯乙双胍治疗的敏感性增加。更重要的是，这种联合治疗在体外对 CDK4/6 抑制剂获得耐药性的 ESCC 细胞和异种移植肿瘤中具有强大的疗效。我们的发现揭示了一种通过靶向 ESCC 中失调的 Fbxo4-cyclin D1 轴以及对 CDK4/6 抑制剂耐药的癌症的谷氨酰胺分解和线粒体呼吸进行癌症治疗的分子基础。
