CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin

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; Micol Eleonora Fiori; Ruggero De Maria; 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

iScience. 2021 May 29;24(6):102664. doi: 10.1016/j.isci.2021.102664. eCollection 2021 Jun 25.

Authors

Simone Di Franco¹, Barbara Parrino², Miriam Gaggianesi¹, Vincenzo Davide Pantina¹, Paola Bianca¹, Annalisa Nicotra¹, Laura Rosa Mangiapane¹, Melania Lo Iacono¹, Gloria Ganduscio¹, Veronica Veschi¹, Ornella Roberta Brancato³, Antonino Glaviano¹, Alice Turdo³, Irene Pillitteri¹, Lorenzo Colarossi⁴, Stella Cascioferro², Daniela Carbone², Camilla Pecoraro², Micol Eleonora Fiori⁵, Ruggero De Maria^{6

7}, Matilde Todaro³, Isabella Screpanti⁸, Girolamo Cirrincione², Patrizia Diana², Giorgio Stassi¹

Affiliations

¹ Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Università degli Studi di Palermo, Palermo, Italy.
² Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy.
³ Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy.
⁴ Pathology Unit, Mediterranean Institute of Oncology, Viagrande, Catania, Italy.
⁵ Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
⁶ Institute of General Pathology, Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Roma, Italy.
⁷ Policlinico A Gemelli, Lazio, Roma, Italy.
⁸ Department of Molecular Medicine, Sapienza University, Rome, Italy.

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.