Considering the many routes through which PI3K–AKT can be activated, its robust link to LEPR signalling in driving oncogenic RAS tumours to an invasive SCC state was surprising and suggested that, in this context, LEPR–leptin signalling has a profound role in orchestrating the PI3K–AKT cascade and fuelling SCC tumour growth. The gene discussed is PIK3CA; the disease is neoplasm.