使用 Venetoclax 靶向 BCL2 可增强 KRASG12D 抑制剂 MRTX1133 在胰腺癌中的疗效。
Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer.
发表日期：2024 Aug 13
作者：
Jeffrey H Becker, Anastasia E Metropulos, Christina Spaulding, Alejandra M Marinelarena, Mario A Shields, Daniel R Principe, Thao D Pham, Hidayatullah G Munshi
来源：
CANCER RESEARCH
摘要：
目前正在对带有 KRASG12D 突变的胰腺导管腺癌 (PDAC) 肿瘤患者进行 MRTX1133 的评估。联合策略有可能增强 MRTX1133 的功效，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，并赋予对 FDA 批准的 BCL2 抑制剂 Venetoclax 的敏感性。 MRTX1133 和 Venetoclax 联合治疗导致 3D 培养物中的细胞死亡和生长抑制。联合治疗诱导细胞凋亡需要 BIM。一致地，在用 MRTX1133 治疗的肿瘤中诱导了 BIM，并且 Venetoclax 增强了 MRTX1133 的体内功效。 Venetoclax 还可以在 3D 培养物中使 MRTX1133 耐药的 PDAC 细胞对 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 患者中 MRTX1133 和 Venetoclax 的临床测试提供了理论依据。
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.