PO.CL07.04 · 临床研究
选择性YAP/TEAD抑制剂TY-1054增强KRAS抑制剂或Trop2-ADC在多种实体瘤中的疗效
The selective YAP/TEAD inhibitor TY-1054 enhances the efficacy of KRAS inhibitors or Trop2-ADC in multiple solid tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：KRAS是与人类癌症相关的最常见体细胞突变之一。YAP/TEAD激活是对多种靶向治疗产生耐药的主要原因。近期，YAP/TEAD信号被确认为一个合成致死靶点，可增强KRAS G12C抑制剂的疗效。TY-1054是由TYK Medicines Inc.开发的强效YAP/TEAD抑制剂。
结果：1. TY-1054不仅在非小细胞肺癌(NSCLC) H1373和H2122细胞中增强了FDA批准的KRAS G12C抑制剂Adagrasib和Sotorasib的疗效，还在NSCLC H1972和H2122细胞中增强了Divarasib(GDC-6036)和泛KRAS抑制剂Daroxonrasib(RMC-6236)的疗效。2. TY-1054不仅在体外和体内增强了KRAS G12D抑制剂RMC-9805在SU.86.86(PDAC，KRAS G12D)中的疗效，还在体外和体内增强了泛KRAS抑制剂Daraxonrasib在SU.86.86中的疗效。3. TY-1054增强了cetuximab在头颈部鳞状细胞癌(HNSCC) Cal33细胞中的疗效。4. TY-1054增强了Trop2-ADC(SKB264/Sac-TMT)在三阴性乳腺癌(TNBC)(MDA-MB 231和HCC1806)、NSCLC(H1975和HCC827)以及trastuzumab耐药乳腺癌(JIMT-1)细胞中的疗效。总之，TY-1054具有潜在的宽治疗窗口，目前正在中国的患者中进行评估。2024年已获得美国FDA的IND许可。本研究为在人类临床试验中检验TY-1054与KRAS抑制剂或Trop2-ADC的联合疗法提供了有力的理论依据。TY-1054临床试验的成功实施将为精准肿瘤学提供一个强有力的解决方案。
# Shengli Dong和Zhengfei Guo对本工作贡献相同。
* 通讯作者：Shengli Dong博士；TYK Medicines Inc.；中国浙江省长兴县华溪大道778号D栋，邮编313100。电话：86 17772745590；电子邮件：shengli.dong@tykmedicines.com。
查看英文原文 English abstract
Introduction: KRAS is one of the most common somatic mutations associated with human cancers. YAP/TEAD activation is a major cause of resistance to various targeted therapies. Recently, YAP/TEAD signaling has been identified as a synthetic lethal target that can enhance the efficacy of KRAS G12C inhibitors. TY-1054 is a potent YAP/TEAD inhibitor developed by TYK Medicines Inc.
Results: 1. TY-1054 not only enhanced the efficacy of FDA-approved KRAS G12C inhibitors, Adagrasib and Sotorasib, in Non-Small Cell Lung Cancer (NSCLC) H1373 and H2122 cells, but also enhanced the efficacy of Divarasib (GDC-6036) and pan-KRASi Daroxonrasib (RMC-6236) in NSCLC H1972 and H2122 cells. 2. TY-1054 not only enhanced the efficacy of KRAS G12Di RMC-9805 in SU.86.86 (PDAC, KRAS G12D) in vitro and in vivo, but also enhanced the efficacy of pan-KRASi Daraxonrasib in SU.86.86 in vitro and in vivo. 3. TY-1054 enhances cetuximab efficacy in head and neck squamous cell carcinoma (HNSCC) Cal33 cells. 4. TY-1054 enhances the efficacy of Trop2-ADC (SKB264/Sac-TMT) in triple-negative breast cancer (TNBC) (MDA-MB 231 and HCC1806), NSCLC (H1975 and HCC827), and trastuzumab-resistant breast cancer (JIMT-1) cells. In summary, TY-1054 has a potentially wide therapeutic window and is currently being evaluated in patients in China. IND clearance from the US FDA was received in 2024. This study provides a strong rationale for testing the combination therapy of TY-1054 and KRAS inhibitors or Trop2-ADC in human clinical trials. The successful execution of the TY-1054 clinical trial will provide a powerful solution for precision oncology.
# Shengli Dong and Zhengfei Guo contributed equally to this work.
* Correspondence to: Shengli Dong, Ph.D.; TYK Medicines Inc.; Block D, No. 778 Huaxi Avenue, Changxing, Zhejiang, P. R. China, 313100. Tel: 86 17772745590; e-mail: shengli.dong@tykmedicines.com.
利益披露 Disclosure
S. Dong,
TYK Medicines, Inc. Employment, Stock Option, ), Patent.
Z. Guo,
TYK Medicines, Inc. Employment.
Z. He,
TYK Medicines, Inc. Employment.
A. Liang,
TYK Medicines, Inc. Employment, Stock Option, Patent.
M. Li,
TYK Medicines, Inc. Employment, Stock Option, Patent.
G. Liu,
TYK Medicines, Inc. Employment, Patent.
C. Zhou,
TYK Medicines, Inc. Employment.
Y. Yu,
TYK Medicines Employment.
X. Yang,
TYK Medicines Employment.
H. Li,
TYK Medicines, Inc Employment.
C. Niu,
TYK Medicines, Inc. Employment, Stock Option, Patent.
S. Chen,
TYK Medicines, Inc. Employment, Stock Option, ), Patent.
J. Li,
TYK Medicines, Inc. Employment, g., Board of Directors, non-salaried role), Stock Option, Patent.
Y. Wu,
TYK Medicines, Inc. Employment, g., Board of Directors, non-salaried role), Stock, Stock Option, Other Business Ownership, Patent, Trademark, Copyright, Other Intellectual Property.