Institute of Pathology, Ludwig-Maximilians-Universität Munich, Munich, Germany.
Department of Urology, Ludwig-Maximilians-Universität Munich, Munich, Germany.
Cancer Sci. 2019 Aug;110(8):2529-2539. doi: 10.1111/cas.14077. Epub 2019 Jun 17.
Patients with advanced colorectal cancer often are treated with systemic cytotoxic therapy using fluorouracil (5-FU), oxaliplatin, irinotecan, and FOLFOX or FOLFIRI combination protocols. Additionally, signaling pathways that are active in colorectal cancer can be therapeutically targeted. Herein, we examined whether chemotherapy impacts on WNT, MAPK and NOTCH signaling pathways in xenograft models of colon cancer. Furthermore, we tested whether combining chemotherapy with MAPK and NOTCH inhibition has superior therapeutic effects. We show that colon cancer cells with high WNT, MAPK and NOTCH activity are variably affected but generally persist in xenograft tumors under different chemotherapeutic regimens, indicating limited effects of cytotoxic therapy on oncogenic signaling pathways. Although these results provided a rationale to additionally target pathway activity, we found no significant increase in therapy response when combining MAPK and NOTCH inhibition with fluorouracil chemotherapy. We attribute this finding to a decrease in tumor cell proliferation upon MAPK and NOTCH inhibition, resulting in reduced effectiveness of cytotoxic treatment. Therapeutic benefits of combining chemotherapy with targeting of oncogenic signaling pathways must therefore be critically evaluated for patients with colorectal cancer.
晚期结直肠癌患者常采用氟尿嘧啶（5-FU）、奥沙利铂、伊立替康和 FOLFOX 或 FOLFIRI 联合方案进行全身细胞毒性治疗。此外，结直肠癌中活跃的信号通路可以作为治疗靶点。在此，我们研究了化疗是否会影响结肠癌异种移植模型中的 WNT、MAPK 和 NOTCH 信号通路。此外，我们还测试了化疗联合 MAPK 和 NOTCH 抑制是否具有更好的治疗效果。我们发现，高 WNT、MAPK 和 NOTCH 活性的结肠癌细胞受到不同程度的影响，但在不同的化疗方案下，异种移植肿瘤中通常仍然存在，表明细胞毒性治疗对致癌信号通路的影响有限。尽管这些结果为进一步靶向通路活性提供了依据，但我们发现 MAPK 和 NOTCH 抑制联合氟尿嘧啶化疗并没有显著增加治疗反应。我们将这一发现归因于 MAPK 和 NOTCH 抑制导致肿瘤细胞增殖减少，从而降低了细胞毒性治疗的效果。因此，对于结直肠癌患者，必须对化疗联合致癌信号通路靶向治疗的获益进行严格评估。
