RAF/MEK夹具Avutometinib的体外和体内活性与子宫癌中的FAK抑制
Preclinical in vitro and in vivo activity of the RAF/MEK clamp avutometinib in combination with FAK inhibition in uterine carcinosarcomas
影响因子:4.10000
分区:医学2区 Top / 妇产科学1区 肿瘤学2区
发表日期:2024 Aug
作者:
Cem Demirkiran, Michelle Greenman, Stefania Bellone, Blair McNamara, Tobias Max Philipp Hartwich, Diego Manavella, Levent Mutlu, Margherita Zipponi, Yang Yang-Hartwich, Kevin Yang, Elena Ratner, Peter E Schwartz, Silvia Coma, Jonathan Pachter, Alessandro D Santin
摘要
子宫癌（UCS）是罕见的生物学侵袭性肿瘤。由于UC可能在RAS/MAPK途径基因中携带突变，因此我们评估了RAF/MEK夹具的临床前体外和体内功效，并结合了焦点粘附激酶（FAK）抑制剂（FAK）抑制作用，而焦点粘附器（FAK）抑制作用defs-4718在多个初级的UCS Cell lines-exects-exectsssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss. 5个主要UCS细胞系的景观。使用细胞活力和细胞周期测定对原代UCS细胞系进行了细胞活力和细胞周期测定，评估了Avutometinib±FAK抑制剂的体外活性。使用蛋白质印迹测定法进行了机械研究，而体内实验则在用口服粘贴的UCS肿瘤轴承完成，该肿瘤轴承的小鼠通过口服粘液抑制剂进行了。WES结果表明，多个UCS携带了遗传变化，包括KRAS，PTK2，PTK2，BRAF，BRAF，MAP2K和MAP2K1，潜在的Sensitlib and and and和RAKINIB和RAKITING/MEK INKITING和RAKITING/MEK INKITING/MEK INKITING/MEK INKITING/MEK INKITLIB和RAF。五个UCS细胞系中有四个在单独使用或组合使用时表现出对FAK和/或RAF/MEK抑制的体外敏感性。通过Western印迹分析，UCS细胞系暴露于Defactinib/Avutometinib的组合中，磷酸化（P）-FAK以及P-ERK降低。在体内，与单一药物治疗和对照组相比，UCS异种移植物中的单一药物治疗和对照组的组合表现出优质的肿瘤生长抑制和更长的存活率。avutometinib和Defactinib的组合表现出在体外和体外和抗肿瘤的抗timor Antigraft Antigr Antigr Antigr Antigr Antimer Antirtial and ucs and ucs and ucs and ucs and tone and tone and ucs and tone and ucs and tone。
Abstract
Uterine carcinosarcomas (UCS) are rare, biologically aggressive tumors. Since UCS may harbor mutations in RAS/MAPK pathway genes we evaluated the preclinical in vitro and in vivo efficacy of the RAF/MEK clamp avutometinib in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718 against multiple primary UCS cell lines and xenografts.Whole-exome-sequencing (WES) was used to evaluate the genetic landscape of 5 primary UCS cell lines. The in vitro activity of avutometinib ± FAK inhibitor was evaluated using cell viability and cell cycle assays against primary UCS cell lines. Mechanistic studies were performed using western blot assays while in vivo experiments were completed in UCS tumor bearing mice treated with avutometinib ± FAK inhibitor by oral gavage.WES results demonstrated multiple UCS cell lines harbor genetic alterations including KRAS, PTK2, BRAF, MAP2K, and MAP2K1, potentially sensitizing to FAK and RAF/MEK inhibition. Four out of five of the UCS cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition when used alone or in combination. By western blot assays, exposure of UCS cell lines to the combination of defactinib/avutometinib demonstrated decreased phosphorylated (p)-FAK as well as decreased p-ERK. In vivo, the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition and longer survival compared to single agent treatment and controls starting at day 10 (p < 0.002) in UCS xenografts.The combination of avutometinib and defactinib demonstrates promising in vitro and in vivo anti-tumor activity against primary UCS cell lines and xenografts.