CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin

iScience

Matilde Todaro¹  Barbara Parrino²  Camilla Pecoraro²  Stella Cascioferro²  Patrizia Diana²  Giorgio Stassi²  Daniela Carbone²  Ornella Roberta Brancato³  Alice Turdo³  Isabella Screpanti³  Girolamo Cirrincione⁴  Micol Eleonora Fiori⁵  Vincenzo Davide Pantina⁶  Miriam Gaggianesi⁶  Veronica Veschi⁶  Antonino Glaviano⁶  Annalisa Nicotra⁶  Paola Bianca⁶  Laura Rosa Mangiapane⁶  Simone Di Franco⁶  Melania Lo Iacono⁶  Irene Pillitteri⁶  Gloria Ganduscio⁶  Ruggero De Maria⁷  Lorenzo Colarossi⁸ 

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

关键词: Cancer;    Cell Biology;    Drugs;    Molecular Physiology;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown