Colorectal Cancer (CRC) develops in the large intestine often together with the loss of the functional P53 gene. CRC is ranked third among the most common cancers affecting men and women worldwide. The leucine-rich repeat G-protein coupled receptor (LGR5) is a marker of colorectal cancer stem cells. Also, it has been reported that depletion of Centromeric protein A (CENPA) in proliferative P53 null cancer cells causes cell death. From those backgrounds, we aimed to understand the synergistic lethality of CENPA and LGR5+ cells in gastrointestinal cancers and propose to eliminate cancer cells by simultaneously inhibiting CENPA and LGR5+ cells using mouse/human organoids and mouse in vivo models. To confirm our hypothesis, we knocked down CENPA transcripts in the gastrointestinal tumour organoids. But contrary to previous reports, the CENPA depletion did not induce cell death of P53 null gastrointestinal tumour cells. On the other hand, the depletion of LGR5+ cells inhibited the growth of tumour organoids. Now, we are working on targeting the Lgr5+ gastrointestinal tumour stem cells.