In pre-clinical RCC models, including those with VHL alterations, resistance to PT2399 (a preclinical derivative of belzutifan) was associated with lower HIF-2α levels relative to sensitive cells (23% vs. 83%, p < 0.0001) but higher expression of HIF1A encoding for HIF-1α, which is another HIF that is activated during hypoxic stress [20,21]. The gene discussed is VHL; the disease is renal cell carcinoma.