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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Checkpoint Kinase 1 / antagonists & inhibitors*
  • Checkpoint Kinase 1 / genetics
  • Checkpoint Kinase 1 / metabolism
  • Forkhead Box Protein M1 / genetics
  • Forkhead Box Protein M1 / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mitosis / drug effects*
  • Multiprotein Complexes
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazines / pharmacology*
  • Pyrazoles / pharmacology*
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Lin54 protein, human
  • MYBL2 protein, human
  • Multiprotein Complexes
  • Protein Kinase Inhibitors
  • Pyrazines
  • Pyrazoles
  • Trans-Activators
  • prexasertib
  • CHEK1 protein, human
  • Checkpoint Kinase 1