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Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer
Cancer Research ( IF 12.5 ) Pub Date : 2024-08-13 , DOI: 10.1158/0008-5472.can-23-3574 Jeffrey H Becker 1 , Anastasia E Metropulos 2 , Christina Spaulding 2 , Alejandra M Marinelarena 2 , Mario A Shields 2 , Daniel R Principe 2 , Thao D Pham 2 , Hidayatullah G Munshi 2
Cancer Research ( IF 12.5 ) Pub Date : 2024-08-13 , DOI: 10.1158/0008-5472.can-23-3574 Jeffrey H Becker 1 , Anastasia E Metropulos 2 , Christina Spaulding 2 , Alejandra M Marinelarena 2 , Mario A Shields 2 , Daniel R Principe 2 , Thao D Pham 2 , Hidayatullah G Munshi 2
Affiliation
MRTX1133 is currently being evaluated in patients with pancreatic ductal adenocarcinoma (PDAC) tumors harboring a KRASG12D mutation. Combination strategies have the potential to enhance the efficacy of MRTX1133 to further promote cell death and tumor regression. In this study, we demonstrated that MRTX1133 increased the levels of the pro-apoptotic protein BIM in PDAC cells and conferred sensitivity to the FDA-approved BCL2 inhibitor venetoclax. Combined treatment with MRTX1133 and venetoclax resulted in cell death and growth suppression in 3D cultures. BIM was required for apoptosis induced by the combination treatment. Consistently, BIM was induced in tumors treated with MRTX1133, and venetoclax enhanced the efficacy of MRTX1133 in vivo. Venetoclax could also re-sensitize MRTX1133-resistant PDAC cells to MRTX1133 in 3D cultures, and tumors established from resistant cells responded to the combination of MRTX1133 and venetoclax. These results provide a rationale for the clinical testing of MRTX1133 and venetoclax in PDAC patients.
中文翻译:
用 Venetoclax 靶向 BCL2 可增强 KRASG12D 抑制剂MRTX1133在胰腺癌中的疗效
目前正在对携带 KRASG12D 突变的胰腺导管腺癌 (PDAC) 肿瘤患者MRTX1133进行评估。联合治疗策略有可能增强 MRTX1133 的疗效,从而进一步促进细胞死亡和肿瘤消退。在这项研究中,我们证明MRTX1133增加了 PDAC 细胞中促凋亡蛋白 BIM 的水平,并赋予了对 FDA 批准的 BCL2 抑制剂维奈托克的敏感性。MRTX1133 和 venetoclax 联合处理导致 3D 培养物中的细胞死亡和生长抑制。联合治疗诱导的细胞凋亡需要 BIM。一致地,BIM 在用 MRTX1133 治疗的肿瘤中被诱导,维奈托克增强了 MRTX1133 在体内的疗效。Venetoclax 还可以使MRTX1133耐药的 PDAC 细胞对 3D 培养物中的 MRTX1133 重新敏感,并且由耐药细胞建立的肿瘤对 MRTX1133 和 venetoclax 的组合有反应。这些结果为 PDAC 患者 MRTX1133 和 venetoclax 的临床测试提供了理论依据。
更新日期:2024-08-13
中文翻译:
用 Venetoclax 靶向 BCL2 可增强 KRASG12D 抑制剂MRTX1133在胰腺癌中的疗效
目前正在对携带 KRASG12D 突变的胰腺导管腺癌 (PDAC) 肿瘤患者MRTX1133进行评估。联合治疗策略有可能增强 MRTX1133 的疗效,从而进一步促进细胞死亡和肿瘤消退。在这项研究中,我们证明MRTX1133增加了 PDAC 细胞中促凋亡蛋白 BIM 的水平,并赋予了对 FDA 批准的 BCL2 抑制剂维奈托克的敏感性。MRTX1133 和 venetoclax 联合处理导致 3D 培养物中的细胞死亡和生长抑制。联合治疗诱导的细胞凋亡需要 BIM。一致地,BIM 在用 MRTX1133 治疗的肿瘤中被诱导,维奈托克增强了 MRTX1133 在体内的疗效。Venetoclax 还可以使MRTX1133耐药的 PDAC 细胞对 3D 培养物中的 MRTX1133 重新敏感,并且由耐药细胞建立的肿瘤对 MRTX1133 和 venetoclax 的组合有反应。这些结果为 PDAC 患者 MRTX1133 和 venetoclax 的临床测试提供了理论依据。