We have recently found that mutant PIK3CA licensed TRAIL and CD95L to induce an amoeboid morphology in CRC cells, which is associated with increased invasiveness in vitro.9 Here, we show that targeting of the aberrantly active PI3K/Akt signaling pathway in TRAIL resistant, PIK3CA-mutated CRC cells only partially restored death receptor-triggered apoptosis induction. The gene discussed is PIK3CA; the disease is colorectal carcinoma.