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CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin

  • Authors: Di Franco, Simone; Parrino, Barbara; Gaggianesi, Miriam; Pantina, Vincenzo Davide; Bianca, Paola; Nicotra, Annalisa; Mangiapane, Laura Rosa; Lo Iacono, Melania; Ganduscio, Gloria; Veschi, Veronica; Brancato, Ornella Roberta; Glaviano, Antonino; Turdo, Alice; Pillitteri, Irene; Colarossi, Lorenzo; Cascioferro, Stella; Carbone, Daniela; Pecoraro, Camilla; Fiori, Micol Eleonora; De Maria, Ruggero; Todaro, Matilde; Screpanti, Isabella; Cirrincione, Girolamo; Diana, Patrizia; Stassi, Giorgio
  • Publication year: 2021
  • Type: Articolo in rivista
  • OA Link: http://hdl.handle.net/10447/513729

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.