Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, H-1091, Budapest, Hungary.
KINETO Lab Ltd, H-1037, Budapest, Hungary.
Br J Cancer. 2024 Apr;130(6):1059-1072. doi: 10.1038/s41416-024-02586-x. Epub 2024 Jan 26.
Inhibition of mutant KRAS challenged cancer research for decades. Recently, allele-specific inhibitors were approved for the treatment of KRAS-G12C mutant lung cancer. However, de novo and acquired resistance limit their efficacy and several combinations are in clinical development. Our study shows the potential of combining G12C inhibitors with farnesyl-transferase inhibitors.
Combinations of clinically approved farnesyl-transferase inhibitors and KRAS G12C inhibitors are tested on human lung, colorectal and pancreatic adenocarcinoma cells in vitro in 2D, 3D and subcutaneous xenograft models of lung adenocarcinoma. Treatment effects on migration, proliferation, apoptosis, farnesylation and RAS signaling were measured by histopathological analyses, videomicroscopy, cell cycle analyses, immunoblot, immunofluorescence and RAS pulldown.
Combination of tipifarnib with sotorasib shows synergistic inhibitory effects on lung adenocarcinoma cells in vitro in 2D and 3D. Mechanistically, we present antiproliferative effect of the combination and interference with compensatory HRAS activation and RHEB and lamin farnesylation. Enhanced efficacy of sotorasib in combination with tipifarnib is recapitulated in the subcutaneous xenograft model of lung adenocarcinoma. Finally, combination of additional KRAS G1C and farnesyl-transferase inhibitors also shows synergism in lung, colorectal and pancreatic adenocarcinoma cellular models.
Our findings warrant the clinical exploration of KRAS-G12C inhibitors in combination with farnesyl-transferase inhibitors.
抑制突变型 KRAS 一直是癌症研究的挑战。最近，针对 KRAS-G12C 突变型肺癌的等位基因特异性抑制剂已获得批准。然而，原发和获得性耐药限制了它们的疗效，几种联合治疗正在临床开发中。我们的研究表明，KRAS-G12C 抑制剂与法尼基转移酶抑制剂联合具有潜力。
在体外二维、三维和肺腺癌皮下移植模型中，检测临床批准的法尼基转移酶抑制剂与 KRAS G12C 抑制剂联合对人肺、结直肠和胰腺腺癌细胞的作用。通过组织病理学分析、视频显微镜、细胞周期分析、免疫印迹、免疫荧光和 RAS 下拉实验测量对迁移、增殖、凋亡、法尼基化和 RAS 信号的治疗效果。
Tipifarnib 与 sotorasib 联合使用对体外二维和三维肺腺癌细胞具有协同抑制作用。从机制上讲，我们提出了联合用药的抗增殖作用，并干扰了补偿性 HRAS 激活和 RHEB 和 lamin 法尼基化。sotorasib 与 tipifarnib 联合使用在肺腺癌皮下移植模型中重现了增强的疗效。最后，其他 KRAS G1C 和法尼基转移酶抑制剂的联合也在肺、结直肠和胰腺腺癌细胞模型中显示出协同作用。
我们的发现证明了 KRAS-G12C 抑制剂与法尼基转移酶抑制剂联合应用的临床探索价值。
