WEE1 Inhibitor Adavosertib Exerts Antitumor Effects on Colorectal Cancer, Especially in Cases with p53 Mutations

Area of Science:

• Oncology
• Cell Biology
• Cancer Immunology

Background:

• WEE1 kinase regulates the G2/M cell cycle checkpoint, and its inhibition can trigger apoptosis by forcing mitosis with unrepaired DNA.
• The impact of WEE1 inhibitors on the tumor immune microenvironment in colorectal cancer (CRC) is not well understood.

Purpose of the Study:

• To investigate the correlation between WEE1 expression and CRC clinicopathological features.
• To evaluate the antitumor efficacy and immune-modulating effects of a WEE1 inhibitor in CRC models.

Main Methods:

• Analysis of WEE1 expression in patient-derived CRC specimens.
• In vitro studies using CRC cell lines to assess proliferation, cell cycle, and apoptosis.
• In vivo studies using an orthotopic CRC mouse model treated with a WEE1 inhibitor.
• RNA sequencing and immunohistochemistry on mouse tumors to analyze immune and stromal changes.

Main Results:

• WEE1 expression did not correlate with CRC clinicopathological features.
• The WEE1 inhibitor reduced CRC cell proliferation, increased G2/M phase arrest and apoptosis, particularly in p53-mutated cell lines.
• Tumor volume was significantly reduced in WEE1 inhibitor-treated mice.
• WEE1 inhibition activated anti-tumor immunity and suppressed stromal reactions within the tumor microenvironment.

Conclusions:

• WEE1 inhibitors demonstrate significant antitumor activity in CRC models.
• The therapeutic potential of WEE1 inhibitors is more pronounced in CRC with p53 mutations.
• WEE1 inhibition modulates the tumor immune microenvironment, suggesting a role in immunotherapy for CRC.