Song Xinxin, Zhou Zhuan, Elmezayen Ammar, Wu Runliu, Yu Chunhua, Gao Boning, Minna John D, Westover Kenneth D, Zeh Herbert J, Kroemer Guido, Heasley Lynn E, Kang Rui, Tang Daolin
Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Sci Adv. 2024 Dec 13;10(50):eadq4274. doi: 10.1126/sciadv.adq4274. Epub 2024 Dec 11.
Direct targeting of the -mutant protein using covalent inhibitors (G12Ci) acts on human non-small cell lung cancer (NSCLC). However, drug resistance is an emerging concern in this approach. Here, we show that MRTX849, a covalent inhibitor targeting the mutation, leads to the reactivation of the mitogen-activated protein kinase signaling pathway in MRTX849-resistant NSCLC and pancreatic ductal adenocarcinoma. A genome-wide CRISPR screen revealed that the adenosine triphosphate binding cassette transporter ABCC1 mediates MRTX849 resistance. Functional studies demonstrated that the transcription factor JUN drives ABCC1 expression, resulting in multidrug resistance. An unbiased drug screen identified the tyrosine kinase inhibitor dasatinib that potentiates MRTX849 efficacy by inhibiting SRC-dependent JUN activation, avoiding multidrug resistance and tumor suppression in vitro as well as in suitable preclinical mouse models and patient-derived organoids. SRC inhibitors (DGY-06-116, dasatinib, and bosutinib) also exhibit synergistic effects with MRTX849 in eliminating various tumor cell lines carrying mutations. Thus, SRC inhibitors amplify the therapeutic utility of G12Ci.
使用共价抑制剂（G12Ci）直接靶向 - 突变蛋白可作用于人类非小细胞肺癌（NSCLC）。然而，耐药性是这种方法中一个新出现的问题。在此，我们表明，靶向 突变的共价抑制剂MRTX849可导致MRTX849耐药的NSCLC和胰腺导管腺癌中的丝裂原活化蛋白激酶信号通路重新激活。全基因组CRISPR筛选显示，三磷酸腺苷结合盒转运蛋白ABCC1介导MRTX849耐药。功能研究表明，转录因子JUN驱动ABCC1表达，导致多药耐药。一项无偏倚的药物筛选鉴定出酪氨酸激酶抑制剂达沙替尼，其通过抑制SRC依赖性JUN激活来增强MRTX849的疗效，在体外以及合适的临床前小鼠模型和患者来源的类器官中避免多药耐药并抑制肿瘤。SRC抑制剂（DGY - 06 - 116、达沙替尼和博舒替尼）在消除各种携带 突变的肿瘤细胞系方面也与MRTX849表现出协同作用。因此，SRC抑制剂增强了G12Ci的治疗效用。
