VHL and neoplasm: In order to effectively manage the resistance, a clinical program should implement an initial rigorous upfront investigation followed by continual follow-up including genomic testing to confirm VHL status and search for compensatory mechanisms such as HDAC8 and CHD1L, as well as traditional follow-up including clinical and radiologic assessment through RECIST criteria and a more sophisticated approach including serial circulating tumor DNA assays to detect mutations underlying the resistance (70).