6533b7d5fe1ef96bd12649ba

RESEARCH PRODUCT

CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin

Girolamo CirrincioneLaura Rosa MangiapaneGiorgio StassiAlice TurdoIrene PillitteriGloria GanduscioVeronica VeschiMicol E. FioriAntonino GlavianoPatrizia DianaDaniela CarboneSimone Di FrancoCamilla PecoraroOrnella Roberta BrancatoAnnalisa NicotraRuggero De MariaBarbara ParrinoLorenzo ColarossiIsabella ScrepantiStella CascioferroMelania Lo IaconoMiriam GaggianesiPaola BiancaMatilde TodaroVincenzo Davide Pantina

subject

0301 basic medicineCell cycle checkpointColorectal cancerScienceSettore MED/50 - Scienze Tecniche Mediche Applicate02 engineering and technologyGenotoxic StressArticleMolecular Physiology03 medical and health sciencesSettore MED/04 - PATOLOGIA GENERALERabusertibmedicineClonogenic assayCancerMultidisciplinarybusiness.industryQWnt signaling pathwayDrugsCancerCell Biology021001 nanoscience & nanotechnologymedicine.disease030104 developmental biologyCancer researchSettore MED/46 - Scienze Tecniche Di Medicina Di LaboratorioStem cell0210 nano-technologybusinesscolorectal cancer cancer stem cells alkaloids DNA damage repair CHK1.

description

Summary Limited therapeutic options are available for advanced colorectal cancer (CRC). Herein, we report that exposure to a neo-synthetic bis(indolyl)thiazole alkaloid analog, nortopsentin 234 (NORA234), leads to an initial reduction of proliferative and clonogenic potential of CRC sphere cells (CR-CSphCs), followed by an adaptive response selecting the CR-CSphC-resistant compartment. Cells spared by the treatment with NORA234 express high levels of CD44v6, associated with a constitutive activation of Wnt pathway. In CR-CSphC-based organoids, NORA234 causes a genotoxic stress paralleled by G2-M cell cycle arrest and activation of CHK1, driving the DNA damage repair of CR-CSphCs, regardless of the mutational background, microsatellite stability, and consensus molecular subtype. Synergistic combination of NORA234 and CHK1 (rabusertib) targeting is synthetic lethal inducing death of both CD44v6-negative and CD44v6-positive CRC stem cell fractions, aside from Wnt pathway activity. These data could provide a rational basis to develop an effective strategy for the treatment of patients with CRC.

yearjournalcountryeditionlanguage
2021-06-01iScience
https://doi.org/10.1016/j.isci.2021.102664