iScience (Jun 2021)
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
Affiliations
- Simone Di Franco
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Università degli Studi di Palermo, Palermo, Italy
- Barbara Parrino
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
- Miriam Gaggianesi
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Università degli Studi di Palermo, Palermo, Italy
- Vincenzo Davide Pantina
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Università degli Studi di Palermo, Palermo, Italy
- Paola Bianca
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Università degli Studi di Palermo, Palermo, Italy
- Annalisa Nicotra
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Università degli Studi di Palermo, Palermo, Italy
- Laura Rosa Mangiapane
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Università degli Studi di Palermo, Palermo, Italy
- Melania Lo Iacono
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Università degli Studi di Palermo, Palermo, Italy
- Gloria Ganduscio
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Università degli Studi di Palermo, Palermo, Italy
- Veronica Veschi
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Università degli Studi di Palermo, Palermo, Italy
- Ornella Roberta Brancato
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
- Antonino Glaviano
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Università degli Studi di Palermo, Palermo, Italy
- Alice Turdo
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
- Irene Pillitteri
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Università degli Studi di Palermo, Palermo, Italy
- Lorenzo Colarossi
- Pathology Unit, Mediterranean Institute of Oncology, Viagrande, Catania, Italy
- Stella Cascioferro
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
- Daniela Carbone
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
- Camilla Pecoraro
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
- Micol Eleonora Fiori
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
- Ruggero De Maria
- Institute of General Pathology, Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Roma, Italy; Policlinico A Gemelli, Lazio, Roma, Italy
- Matilde Todaro
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
- Isabella Screpanti
- Department of Molecular Medicine, Sapienza University, Rome, Italy
- Girolamo Cirrincione
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
- Patrizia Diana
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
- Giorgio Stassi
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Università degli Studi di Palermo, Palermo, Italy; Corresponding author
- Journal volume & issue
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Vol. 24,
no. 6
p. 102664
Abstract
Summary: 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.
