美国哥伦比亚大学Kenneth P. Olive等研究人员合作揭示RAS-GTP抑制剂在胰腺癌中的肿瘤选择性活性。该项研究成果于2024年4月8日在线发表在《自然》杂志上。

研究人员表示，广谱RAS抑制剂有可能使大约四分之一受RAS突变驱动的人类癌症患者受益。RMC-7977是一种对KRAS、HRAS和NRAS的GTP结合活性形式具有高度选择性的抑制剂，对突变型和野生型（WT）变体均有亲和力（RAS(ON)多选择性）。

由于90%以上的人类胰腺导管腺癌（PDAC）病例是由KRAS的激活突变驱动的，研究人员在一系列PDAC模型中评估了RAS(ON)多选择性抑制剂RMC-7977的治疗潜力。研究人员观察到，在体内耐受性良好的情况下直接抑制RAS后，各模型均具有广泛而明显的抗肿瘤活性。药理分析表明，肿瘤组织与正常组织对RMC-7977的反应存在差异。

经治疗的肿瘤会出现多轮的细胞凋亡和持续的增殖抑制，而正常组织仅出现短暂的增殖减少，没有凋亡的迹象。在自体KPC模型中，RMC-7977治疗显著延长了患者的生存期，但随之而来的是治疗后复发。对复发肿瘤的分析发现，Myc拷贝数增加是一种常见的候选耐药机制，体外联合抑制TEAD可以克服这一机制。

总之，这些数据为在PDAC病例中使用广谱RAS-GTP抑制剂提供了强有力的临床前依据，并为克服单药耐药性找到了一种有希望的候选联合治疗方案。

附：英文原文

Title: Tumor-selective activity of RAS-GTP inhibition in pancreatic cancer

Author: Wasko, Urszula N., Jiang, Jingjing, Dalton, Tanner C., Curiel-Garcia, Alvaro, Edwards, A. Cole, Wang, Yingyun, Lee, Bianca, Orlen, Margo, Tian, Sha, Stalnecker, Clint A., Drizyte-Miller, Kristina, Menard, Marie, Dilly, Julien, Sastra, Stephen A., Palermo, Carmine F., Hasselluhn, Marie C., Decker-Farrell, Amanda R., Chang, Stephanie, Jiang, Lingyan, Wei, Xing, Yang, Yu C., Helland, Ciara, Courtney, Haley, Gindin, Yevgeniy, Muonio, Karl, Zhao, Ruiping, Kemp, Samantha B., Clendenin, Cynthia, Sor, Rina, Vostrejs, William P., Hibshman, Priya S., Amparo, Amber M., Hennessey, Connor, Rees, Matthew G., Ronan, Melissa M., Roth, Jennifer A., Brodbeck, Jens, Tomassoni, Lorenzo, Bakir, Basil, Socci, Nicholas D., Herring, Laura E., Barker, Natalie K., Wang, Junning, Cleary, James M., Wolpin, Brian M., Chabot, John A., Kluger, Michael D., Manji, Gulam A., Tsai, Kenneth Y., Sekulic, Miroslav, Lagana, Stephen M., Califano, Andrea, Quintana, Elsa, Wang, Zhengping, Smith, Jacqueline A. M., Holderfield, Matthew, Wildes, David, Lowe, Scott W., Badgley, Michael A., Aguirre, Andrew J., Vonderheide, Robert H.

Issue&Volume: 2024-04-08

Abstract: Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants (RAS(ON) multi-selective)3. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS4, we assessed the therapeutic potential of the RAS(ON) multi-selective inhibitor RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumor activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumors identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

DOI: 10.1038/s41586-024-07379-z

Source: https://www.nature.com/articles/s41586-024-07379-z