CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin

• Main Authors: 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
• Format: Article
• Language: English
• Published: Elsevier 2021-06-01
• Series: iScience
• Subjects: Cancer; Cell Biology; Drugs; Molecular Physiology
• Online Access: http://www.sciencedirect.com/science/article/pii/S2589004221006325
• ISSN: 2589-0042

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.