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Overexpressed FOXM1 collaborates with MMB to increase WEE1 inhibitor sensitivity in NSCLC

Jian Tan1, Jingbo Ma1, Weiqiang Zhang1

  • 1Department of Thoracic Surgery, Seventh Medical Center of Chinese PLA General Hospital, Beijing, China.

Journal of Thoracic Disease
|July 10, 2023
PubMed
Abstract

Insights

Forkhead box M1 (FOXM1) and MYB-MuvB complex (MMB) interaction enhances sensitivity to WEE1 inhibitors in non-small cell lung cancer (NSCLC). This FOXM1-MMB complex promotes DNA replication stress and activates checkpoints, offering new therapeutic strategies for NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Non-small cell lung cancer (NSCLC) presents a significant mortality challenge.
  • The MYB-MuvB (MMB) complex interacting with forkhead box M1 (FOXM1) is crucial for cell cycle progression.
  • The precise role of the FOXM1-MMB complex in WEE1 inhibitor sensitivity within NSCLC remains largely undetermined.

Purpose of the Study:

  • To elucidate the role of the FOXM1-MMB complex in modulating WEE1 inhibitor sensitivity in NSCLC.
  • To investigate how FOXM1 affects DNA replication stress, DNA damage, and cell cycle checkpoints in response to WEE1 inhibition.
  • To determine the therapeutic implications of targeting the FOXM1-MMB complex in NSCLC treatment.

Main Methods:

  • Quantitative polymerase chain reaction (RT-qPCR) to assess mRNA levels of FOXM1, LIN54, RPA, γH2AX, and CCNB.
  • Western blotting to evaluate corresponding protein expression levels.
  • Cell Counting Kit-8 (CCK-8) assay to determine cell viability and response to AZD-1775 treatment.

Main Results:

  • FOXM1 overexpression significantly decreased cell survival under WEE1 inhibition, an effect reversed by LIN54 knockdown, confirming the necessity of the FOXM1-MMB complex.
  • FOXM1 upregulation intensified DNA replication stress and DNA damage, evidenced by increased RPA and γH2AX expression.
  • The FOXM1-MMB complex was shown to activate G2/M checkpoints by enhancing CCNB expression and promoting WEE1 dephosphorylation, thereby increasing sensitivity to the WEE1 inhibitor AZD-1775.

Conclusions:

  • Overexpressed FOXM1, in conjunction with the MMB complex, enhances WEE1 inhibitor sensitivity in NSCLC.
  • The FOXM1-MMB complex plays a critical regulatory role in NSCLC pathogenesis and response to targeted therapies.
  • Targeting the FOXM1-MMB pathway presents a promising therapeutic strategy for NSCLC patients.
Keywords:
Forkhead box M1 (FOXM1)MYB-MuvB complex (MMB)Wee1-like protein kinase (WEE1)non-small cell lung cancer (NSCLC)

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