TY - JOUR
T1 - CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin
AU - De Maria Marchiano, Ruggero
AU - Fiori, Micol Eleonora
AU - Di Franco, Simone
AU - Parrino, Barbara
AU - Gaggianesi, Miriam
AU - Pantina, Vincenzo Davide
AU - Bianca, Paola
AU - Nicotra, Annalisa
AU - Mangiapane, Laura Rosa
AU - Lo Iacono, Melania
AU - Ganduscio, Gloria
AU - Veschi, Veronica
AU - Brancato, Ornella Roberta
AU - Glaviano, Antonino
AU - Turdo, Alice
AU - Pillitteri, Irene
AU - Colarossi, Lorenzo
AU - Cascioferro, Stella
AU - Carbone, Daniela
AU - Pecoraro, Camilla
AU - Todaro, Matilde
AU - Cirrincione, Girolamo
AU - Diana, Patrizia
AU - Stassi, Giorgio
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Cancer
KW - Cell Biology
KW - Drugs
KW - Molecular Physiology
KW - Cancer
KW - Cell Biology
KW - Drugs
KW - Molecular Physiology
UR - http://hdl.handle.net/10807/183050
U2 - 10.1016/j.isci.2021.102664
DO - 10.1016/j.isci.2021.102664
M3 - Article
VL - 24
SP - 102664-N/A
JO - iScience
JF - iScience
SN - 2589-0042
ER -