Citarella Anna, Catanzaro Giuseppina, Besharat Zein Mersini, Trocchianesi Sofia, Barbagallo Federica, Gosti Giorgio, Leonetti Marco, Di Fiore Annamaria, Coppola Lucia, Autilio Tanja Milena, Spinello Zaira, Vacca Alessandra, De Smaele Enrico, Venneri Mary Anna, Ferretti Elisabetta, Masuelli Laura, Po Agnese
Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy.
Cancers (Basel). 2023 Feb 25;15(5):1471. doi: 10.3390/cancers15051471.
Colorectal cancer (CRC) is a leading cause of cancer-related mortality and chemoresistance is a major medical issue. The epithelial-to-mesenchymal transition (EMT) is the primary step in the emergence of the invasive phenotype and the Hedgehog-GLI (HH-GLI) and NOTCH signaling pathways are associated with poor prognosis and EMT in CRC. CRC cell lines harboring KRAS or BRAF mutations, grown as monolayers and organoids, were treated with the chemotherapeutic agent 5-Fluorouracil (5-FU) alone or combined with HH-GLI and NOTCH pathway inhibitors GANT61 and DAPT, or arsenic trioxide (ATO) to inhibit both pathways. Treatment with 5-FU led to the activation of HH-GLI and NOTCH pathways in both models. In KRAS mutant CRC, HH-GLI and NOTCH signaling activation co-operate to enhance chemoresistance and cell motility, while in BRAF mutant CRC, the HH-GLI pathway drives the chemoresistant and motile phenotype. We then showed that 5-FU promotes the mesenchymal and thus invasive phenotype in KRAS and BRAF mutant organoids and that chemosensitivity could be restored by targeting the HH-GLI pathway in BRAF mutant CRC or both HH-GLI and NOTCH pathways in KRAS mutant CRC. We suggest that in KRAS-driven CRC, the FDA-approved ATO acts as a chemotherapeutic sensitizer, whereas GANT61 is a promising chemotherapeutic sensitizer in BRAF-driven CRC.
结直肠癌（CRC）是癌症相关死亡的主要原因，化疗耐药是一个重大的医学问题。上皮-间质转化（EMT）是侵袭性表型出现的主要步骤，而刺猬索尼信号通路（HH-GLI）和Notch信号通路与CRC的不良预后和EMT相关。携带KRAS或BRAF突变的CRC细胞系，以单层细胞和类器官形式培养，单独用化疗药物5-氟尿嘧啶（5-FU）处理，或与HH-GLI和Notch通路抑制剂GANT61和DAPT联合处理，或用三氧化二砷（ATO）同时抑制这两条通路。在两种模型中，5-FU处理均导致HH-GLI和Notch通路激活。在KRAS突变的CRC中，HH-GLI和Notch信号激活协同增强化疗耐药性和细胞运动性，而在BRAF突变的CRC中，HH-GLI通路驱动化疗耐药和运动性表型。我们随后表明，5-FU在KRAS和BRAF突变的类器官中促进间充质表型，从而促进侵袭性表型，并且通过靶向BRAF突变CRC中的HH-GLI通路或KRAS突变CRC中的HH-GLI和Notch通路，可以恢复化疗敏感性。我们认为，在KRAS驱动的CRC中，FDA批准的ATO可作为化疗增敏剂，而GANT61在BRAF驱动的CRC中是一种有前景的化疗增敏剂。
