Targeting IGF1R Signaling in MTAP-Deficient Kidney Cancer
Abstract
Kidney cancer (or renal cell carcinoma, RCC) is increasing in incidence and one-third of newly diagnosed cases are already metastatic. Metastatic spread of solid tumors makes kidney cancer incurable by surgical resection and consequently more difficult to treat. Despite the development of targeted therapies, most patients develop resistance following an initial response to therapy and eventually succumb to the disease. In recent years, immunotherapy with checkpoint inhibitors have shown considerable potential in the treatment of RCC; however, many issues remain to be resolved, especially identification of patients who are unlikely to show early benefit from the therapy. For these reasons, novel therapeutic approaches are urgently needed to improve the outcomes of RCC patients. Since RCC has emerged as a metabolic disease characterized by dysregulated expression of metabolic enzymes and altered levels of metabolites, efforts are ongoing to understand mechanisms where tumor metabolism is driving the disease progression and resistance. Furthermore, much effort is going towards translating these findings to therapies in order to personalize treatment and to provide tangible benefits to more patients. Through an integrated two-step analysis of RCC metabolic pathways, we have identified dysregulated expression of methylthioadenosine phosphorylase (MTAP) in aggressive RCC. MTAP plays a critical role in polyamine metabolism where it cleaves methylthioadenosine (MTA) to generate precursor substrates for methionine and adenine salvage pathways. An accumulation of cellular MTA has been observed in RCC cells with MTAP loss. Interestingly, MTA is not only a metabolite associated with the polyamine pathway but also serves as an inhibitor of protein arginine methyltransferase. Recent studies have demonstrated a crosstalk between protein post-translational modifications such as methylation and phosphorylation. The crosstalk between methylation and phosphorylation is an important regulatory mechanism in receptor tyrosine kinase signaling. Our preliminary data have demonstrated that knockout of MTAP expression in RCC cell lines increased cell invasion and migration. A decrease of protein-methylation level concomitant with an increase in tyrosine phosphorylation was observed in MTAP-knockout cells. Surprisingly, we noticed an elevation of the immune checkpoint protein PD-L1 after MTAP knockout. Using a phospho-kinase antibody array screen, we identified the type 1 insulin-like growth factor-1 receptor (IGF1R) as the top one molecule regulated by MTAP expression. Given the above observations, we hypothesize that MTAP loss and/or downregulation promotes PD-L1 expression and subsequent RCC progression through IGF1R signaling. Direct inhibition of IGF1R may reduce the aggressive nature of MTAP-deficient RCC and downregulate their PD-L1 expression. The overall objective of this application is to determine whether MTAP deficiency serves as a therapeutic target and our study will provide mechanistic rationales for the combination of IGF1R inhibitors with immunotherapy in advanced RCC patients. To this end, two specific aims are proposed. Aim 1 is to elucidate the molecular basis of MTAP in the regulation of IGF1R signaling and PD-L1 expression. Aim 2 is to determine the bifunctional roles of MTAP in reducing both RCC malignancy and immunosuppression. The scientific premise for this application is evidence-based and target-driven mechanistic research. The proposed study addresses the following research topics under kidney cancer including (1) targeted therapies; (2) immunotherapies; and (3) metabolism. In this application, we will define the novel functions of MTAP and MTA in mediating protein methylation-phosphorylation crosstalk, signal transduction pathways, and posttranscriptional regulation of immune checkpoint proteins. We will also identify the mechanisms by which arginine methylation regulates cell signaling via interplay with tyrosine- phos
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910831
Entities
People
- Ching-hsien Chen
Organizations
- United States Army
- University of California, Davis