Inhibition of WEE1, a key regulator of the G2/M checkpoint of the cell cycle, induces apoptosis by initiating mitosis without repairing DNA damage. However, the effects of WEE1 inhibitors on the tumor immune microenvironment in colorectal cancer (CRC) remain unclear. Here, we investigated the association between WEE1 expression and CRC clinicopathological features using surgically resected CRC specimens and assessed the antitumor effects of a WEE1 inhibitor using CRC cell lines and orthotopic transplantation mouse models. WEE1 expression was not correlated with the clinicopathological features of CRC. The WEE1 inhibitor suppressed cell proliferation in a concentration-dependent manner in all CRC cell lines. It also increased the percentage of cells in the G2/M phase and apoptotic cells, especially in cell lines withp53mutations, but did not alter these cell percentages in mostp53wild-type cell lines. In the orthotopic mouse model of CRC, tumor volume was significantly reduced in the WEE1 inhibitor-treated group compared to that in the control group. RNA sequencing and immunohistochemistry analyses of mouse tumors revealed that treatment with the WEE1 inhibitor activated tumor immunity and suppressed stromal reactions. These results demonstrate the potential antitumor effects of WEE1 inhibitors in CRC, particularly in patients withp53mutations.
WEE1是细胞周期G2/M检查点的关键调控因子，抑制WEE1可通过诱导DNA损伤未修复的细胞进入有丝分裂从而引发细胞凋亡。然而，WEE1抑制剂对结直肠癌肿瘤免疫微环境的影响尚不明确。本研究利用手术切除的结直肠癌标本分析了WEE1表达与临床病理特征的相关性，并通过结直肠癌细胞系及原位移植小鼠模型评估了WEE1抑制剂的抗肿瘤效应。结果显示，WEE1表达与结直肠癌临床病理特征无显著相关性。WEE1抑制剂在所有结直肠癌细胞系中均呈现浓度依赖性的增殖抑制作用，能显著增加G2/M期细胞比例和凋亡细胞比例，尤其在p53突变细胞系中效果显著，而在大多数p53野生型细胞系中未观察到此类变化。在原位移植小鼠模型中，WEE1抑制剂治疗组肿瘤体积较对照组显著缩小。通过RNA测序和免疫组化分析发现，WEE1抑制剂能激活肿瘤免疫并抑制基质反应。这些结果表明WEE1抑制剂在结直肠癌中具有潜在抗肿瘤作用，尤其对p53突变患者可能具有显著疗效。
肿瘤(癌症)患者之家