MMB-FOXM1-driven premature mitosis is required for CHK1 inhibitor sensitivity

  • Cell Rep. 2021 Mar 2;34(9):108808. doi: 10.1016/j.celrep.2021.108808.
Timothy B Branigan  1 ,  David Kozono  2 ,  Amy E Schade  1 ,  Peter Deraska  2 ,  Hembly G Rivas  1 ,  Larissa Sambel  2 ,  Hunter D Reavis  2 ,  Geoffrey I Shapiro  3 ,  Alan D D'Andrea  2 ,  James A DeCaprio  4
Affiliations
  • 1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, MA, USA.
  • 2. Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 3. Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 33657372 DOI: 10.1016/j.celrep.2021.108808
Abstract

To identify genes whose loss confers resistance to Chk1 inhibitors, we perform genome-wide CRISPR-Cas9 screens in non-small-cell lung Cancer (NSCLC) cell lines treated with the Chk1 Inhibitor prexasertib (CHK1i). Five of the top six hits of the screens, MYBL2 (B-MYB), LIN54, FOXM1, cyclin A2 (CCNA2), and CDC25B, are cell-cycle-regulated genes that contribute to entry into Mitosis. Knockout of MMB-FOXM1 complex components LIN54 and FOXM1 reduce CHK1i-induced DNA replication stress markers and premature Mitosis during Late S phase. Activation of a feedback loop between the MMB-FOXM1 complex and CDK1 is required for CHK1i-induced premature Mitosis in Late S phase and subsequent replication catastrophe, indicating that dysregulation of the S to M transition is necessary for Chk1 Inhibitor sensitivity. These findings provide mechanistic insights into small molecule inhibitors currently studied in clinical trials and provide rationale for combination therapies.

Keywords
CDK1; CHK1; FOXM1; LIN54; MYBL2; MuvB; cell cycle checkpoint; non-small-cell lung cancer; prexasertib.
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