https://ror.org/009eqmr18 Department of Molecular Biomedicine, Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV-IPN), México City, Mexico.
Laboratory of Molecular Modeling and Drug Design of the Higher School of Medicine, National Polytechnic Institute, Mexico City, Mexico.
Life Sci Alliance. 2023 Oct 9;6(12). doi: 10.26508/lsa.202302019. Print 2023 Dec.
Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among all human cancers as it is highly resistant to chemotherapy. K-Ras mutations usually trigger the development and progression of PDAC. We hypothesized that compounds stabilizing the KRas4B/PDE6δ complex could serve as PDAC treatments. Using in silico approaches, we identified the small molecules C14 and P8 that reduced K-Ras activation in primary PDAC cells. Importantly, C14 and P8 significantly prevented tumor growth in patient-derived xenotransplants. Combined treatment with C14 and P8 strongly increased cytotoxicity in PDAC cell lines and primary cultures and showed strong synergistic antineoplastic effects in preclinical murine PDAC models that were superior to conventional therapeutics without causing side effects. Mechanistically, C14 and P8 reduced tumor growth by inhibiting AKT and ERK signaling downstream of K-RAS leading to apoptosis, specifically in PDAC cells. Thus, combined treatment with C14 and P8 may be a superior pharmaceutical strategy to improve the outcome of PDAC.
胰腺导管腺癌（PDAC）是所有人类癌症中预后最差的一种，因为它对化疗具有高度耐药性。K-Ras 突变通常会引发 PDAC 的发展和进展。我们假设稳定 KRas4B/PDE6δ 复合物的化合物可以作为 PDAC 的治疗方法。我们通过计算方法鉴定出小分子 C14 和 P8，它们可以减少原代 PDAC 细胞中的 K-Ras 激活。重要的是，C14 和 P8 可显著预防患者来源的异种移植物中的肿瘤生长。C14 和 P8 的联合治疗在 PDAC 细胞系和原代培养物中强烈增加了细胞毒性，并在临床前小鼠 PDAC 模型中显示出强大的协同抗肿瘤作用，优于无副作用的传统疗法。从机制上讲，C14 和 P8 通过抑制 K-RAS 下游的 AKT 和 ERK 信号传导导致细胞凋亡来抑制肿瘤生长，特别是在 PDAC 细胞中。因此，C14 和 P8 的联合治疗可能是改善 PDAC 预后的一种优越的药物治疗策略。
