CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin

Ruggero De Maria Marchiano; Micol Eleonora Fiori; Simone Di Franco; Barbara Parrino; Miriam Gaggianesi; Vincenzo Davide Pantina; Paola Bianca; Annalisa Nicotra; Laura Rosa Mangiapane; Melania Lo Iacono; Gloria Ganduscio; Veronica Veschi; Ornella Roberta Brancato; Antonino Glaviano; Alice Turdo; Irene Pillitteri; Lorenzo Colarossi; Stella Cascioferro; Daniela Carbone; Camilla Pecoraro; Matilde Todaro; Isabella Screpanti; Girolamo Cirrincione; Patrizia Diana; Giorgio Stassi

doi:10.1016/j.isci.2021.102664

CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin

Ruggero De Maria Marchiano, Micol Eleonora Fiori, Simone Di Franco, Barbara Parrino, Miriam Gaggianesi, Vincenzo Davide Pantina, Paola Bianca, Annalisa Nicotra, Laura Rosa Mangiapane, Melania Lo Iacono, Gloria Ganduscio, Veronica Veschi, Ornella Roberta Brancato, Antonino Glaviano, Alice Turdo, Irene Pillitteri, Lorenzo Colarossi, Stella Cascioferro, Daniela Carbone, Camilla PecoraroMatilde Todaro, Isabella Screpanti, Girolamo Cirrincione, Patrizia Diana, Giorgio Stassi

Risultato della ricerca: Contributo in rivista › Articolo in rivista

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.

Lingua originale	English
pagine (da-a)	102664-N/A
Rivista	iScience
Volume	24
DOI	https://doi.org/10.1016/j.isci.2021.102664
Stato di pubblicazione	Pubblicato - 2021

Keywords

Cancer
Cell Biology
Drugs
Molecular Physiology

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10.1016/j.isci.2021.102664

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De Maria Marchiano, R., Fiori, M. E., Di Franco, S., Parrino, B., Gaggianesi, M., Pantina, V. D., Bianca, P., Nicotra, A., Mangiapane, L. R., Lo Iacono, M., Ganduscio, G., Veschi, V., Brancato, O. R., Glaviano, A., Turdo, A., Pillitteri, I., Colarossi, L., Cascioferro, S., Carbone, D., ... Stassi, G. (2021). CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin. iScience, 24, 102664-N/A. https://doi.org/10.1016/j.isci.2021.102664

@article{749b28991cb44d23bc8d27dfb1cf36e1,

title = "CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin",

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.",

keywords = "Cancer, Cell Biology, Drugs, Molecular Physiology, Cancer, Cell Biology, Drugs, Molecular Physiology",

author = "{De Maria Marchiano}, Ruggero and Fiori, {Micol Eleonora} and {Di Franco}, Simone and Barbara Parrino and Miriam Gaggianesi and Pantina, {Vincenzo Davide} and Paola Bianca and Annalisa Nicotra and Mangiapane, {Laura Rosa} and {Lo Iacono}, Melania and Gloria Ganduscio and Veronica Veschi and Brancato, {Ornella Roberta} and Antonino Glaviano and Alice Turdo and Irene Pillitteri and Lorenzo Colarossi and Stella Cascioferro and Daniela Carbone and Camilla Pecoraro and Matilde Todaro and Isabella Screpanti and Girolamo Cirrincione and Patrizia Diana and Giorgio Stassi",

year = "2021",

doi = "10.1016/j.isci.2021.102664",

language = "English",

volume = "24",

pages = "102664--N/A",

journal = "iScience",

issn = "2589-0042",

publisher = "Elsevier Inc.",

}

De Maria Marchiano, R, Fiori, ME, Di Franco, S, Parrino, B, Gaggianesi, M, Pantina, VD, Bianca, P, Nicotra, A, Mangiapane, LR, Lo Iacono, M, Ganduscio, G, Veschi, V, Brancato, OR, Glaviano, A, Turdo, A, Pillitteri, I, Colarossi, L, Cascioferro, S, Carbone, D, Pecoraro, C, Todaro, M, Screpanti, I, Cirrincione, G, Diana, P & Stassi, G 2021, 'CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin', iScience, vol. 24, pagg. 102664-N/A. https://doi.org/10.1016/j.isci.2021.102664

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 - Screpanti, Isabella

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 -

CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin

Abstract

Keywords

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