Drug repurposing in PIK3CA-related overgrowth spectrum: breakthroughs from overgrowth syndromes to kidney disease.

Abstract

Phosphoinositide 3-kinase α (PI3Kα) is a ubiquitous lipid kinase that transduces extracellular growth, proliferation, and metabolism signals. Genes involved in the PI3Kα signaling pathway are frequently mutated in cancer. Apart from malignant conditions, monogenic rare disorders, called PIK3CA-related overgrowth syndromes, are also caused by mosaic mutations in PIK3CA, the gene encoding the catalytic subunit of PI3Kα, resulting in increased signaling promoting abnormal growth and proliferation. Recent studies have shown that alpelisib, a PI3Kα inhibitor initially designed for breast cancer, is also effective at treating PIK3CA-related overgrowth syndrome. Linking rare malformation syndromes and kidney disease, the improvement of kidney function following treatment with alpelisib in a patient with PIK3CA-related overgrowth syndrome with nonspecific glomerular lesions shed light on the involvement of PI3Kα across various nephropathies. Moreover, the identification of a PIK3CA mosaic variant in his glomerular epithelial cells suggested that mosaic variants of the PI3Kα pathway might explain cases of chronic kidney disease of undetermined etiology. Finally, the deleterious role of the PI3Kα pathway also extends to a wide variety of kidney diseases, such as lupus nephritis, diabetes, or autosomal dominant polycystic kidney disease. In unrelated disorders, PI3Kα involvement has been reported in various cell types, such as mesangial, tubular, and immune cells. This review aims at summarizing the available evidence on the involvement of the pathway in monogenic disorders and kidney disease, highlighting PI3Kα as a potential novel therapeutic target in various nephropathies.