The 5-year survival rate of patients with metastatic renal cell carcinoma (mRCC) is <12% due to treatment failure. Therapeutic strategies that overcome resistance to modestly effective drugs for mRCC, such as sorafenib (SF), could improve outcome in mRCC patients. SF is terminally biotransformed by UDP-glucuronosyltransferase-1A9 (A9) mediated glucuronidation, which inactivates SF. In a clinical-cohort and the TCGA-dataset, A9 transcript and/or protein levels were highly elevated in RCC specimens and predicted metastasis and overall-survival. This suggested that elevated A9 levels even in primary tumors of patients who eventually develop mRCC could be a mechanism for SF failure. 4-methylumbelliferone (MU), a choleretic and antispasmodic drug, downregulated A9 and inhibited SF-glucuronidation in RCC cells. Low-dose SF and MU combinations inhibited growth, motility, invasion and downregulated an invasive signature in RCC cells, patient-derived tumor explants and/or endothelial-RCC cell co-cultures; however, both agents individually were ineffective. A9 overexpression made RCC cells resistant to the combination, while its downregulation sensitized them to SF treatment alone. The combination inhibited kidney tumor growth, angiogenesis and distant metastasis, with no detectable toxicity; A9-overexpressing tumors were resistant to treatment. With effective primary tumor control and abrogation of metastasis in preclinical models, the low-dose SF and MU combinations could be an effective treatment option for mRCC patients. Broadly, our study highlights how targeting specific mechanisms that cause the failure of "old" modestly effective FDA-approved drugs could improve treatment response with minimal alteration in toxicity profile.
Oncogenesis. 2020 May 19*** epublish ***
Andre R Jordan, Jiaojiao Wang, Travis J Yates, Sarrah L Hasanali, Soum D Lokeshwar, Daley S Morera, Nagarajarao Shamaladevi, Charles S Li, Zachary Klaassen, Martha K Terris, Muthusamy Thangaraju, Amar B Singh, Mark S Soloway, Vinata B Lokeshwar
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd., Augusta, GA, 30912, USA., Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami-Miller School of Medicine, Miami, 1600 NW 10th Avenue, Miami, FL, 33136, USA., Honors Program in Medical Education, University of Miami-Miller School of Medicine, Miami, 1600 NW 10th Avenue, Miami, FL, 33136, USA., GeneChem Diagnostics Laboratory, Miami, FL, 33157, USA., Department of Surgery, Division of Urology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd., Augusta, GA, 30912, USA., Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Memorial Healthcare System, Aventura, FL, 33180, USA., Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd., Augusta, GA, 30912, USA. .