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.

Di Franco, S., Parrino, B., Gaggianesi, M., Pantina, V.D., Bianca, P., Nicotra, A., et al. (2021). CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin. ISCIENCE, 24(6), 1-17 [10.1016/j.isci.2021.102664].

CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin

Di Franco, Simone;Parrino, Barbara;Gaggianesi, Miriam;Pantina, Vincenzo Davide;Nicotra, Annalisa;Mangiapane, Laura Rosa;Lo Iacono, Melania;Ganduscio, Gloria;Veschi, Veronica;Glaviano, Antonino;Turdo, Alice;Cascioferro, Stella;Carbone, Daniela;Pecoraro, Camilla;Todaro, Matilde;Cirrincione, Girolamo;Diana, Patrizia;Stassi, Giorgio
2021

Abstract

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.
Settore MED/46 - Scienze Tecniche Di Medicina Di Laboratorio
Settore MED/50 - Scienze Tecniche Mediche Applicate
Di Franco, S., Parrino, B., Gaggianesi, M., Pantina, V.D., Bianca, P., Nicotra, A., et al. (2021). CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin. ISCIENCE, 24(6), 1-17 [10.1016/j.isci.2021.102664].
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10447/513729
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