TY - JOUR
T1 - CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin
AU - Di, Franco S.
AU - Parrino, B.
AU - Gaggianesi, M.
AU - Pantina, V. D.
AU - Bianca, P.
AU - Nicotra, A.
AU - Mangiapane, L. R.
AU - Lo, Iacono M.
AU - Ganduscio, G.
AU - Veschi, V.
AU - Brancato, O. R.
AU - Glaviano, A.
AU - Turdo, A.
AU - Pillitteri, I.
AU - Colarossi, L.
AU - Cascioferro, S.
AU - Carbone, D.
AU - Pecoraro, C.
AU - Fiori, Micol Eleonora
AU - De Maria Marchiano, Ruggero
AU - Todaro, M.
AU - Screpanti, I.
AU - Cirrincione, G.
AU - Diana, P.
AU - Stassi, G.
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 - https://publicatt.unicatt.it/handle/10807/183050
UR - https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=85107677419&origin=inward
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85107677419&origin=inward
U2 - 10.1016/j.isci.2021.102664
DO - 10.1016/j.isci.2021.102664
M3 - Article
SN - 2589-0042
VL - 24
SP - 102664-N/A
JO - iScience
JF - iScience
IS - 6
ER -
