Institute of Biopharmaceutical and Health Engineering and Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, People's Republic of China.
Food Science and Technology Program, Department of Life Sciences, BNU-HKBU United International College, Zhuhai, 519087, Guangdong, People's Republic of China.
Cell Death Dis. 2024 Feb 26;15(2):173. doi: 10.1038/s41419-024-06551-7.
Therapeutic targeting of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) has remained a significant challenge in clinical oncology. Direct targeting of KRAS has proven difficult, and inhibition of the KRAS effectors have shown limited success due to compensatory activation of survival pathways. Being a core downstream effector of the KRAS-driven p44/42 MAPK and PI3K/AKT pathways governing intrinsic apoptosis, BAD phosphorylation emerges as a promising therapeutic target. Herein, a positive association of the pBADS99/BAD ratio with higher disease stage and worse overall survival of PDAC was observed. Homology-directed repair of BAD to BADS99A or small molecule inhibition of BADS99 phosphorylation by NCK significantly reduced PDAC cell viability by promoting cell cycle arrest and apoptosis. NCK also abrogated the growth of preformed colonies of PDAC cells in 3D culture. Furthermore, high-throughput screening with an oncology drug library to identify potential combinations revealed a strong synergistic effect between NCK and MEK inhibitors in PDAC cells harboring either wild-type or mutant-KRAS. Mechanistically, both mutant-KRAS and MEK inhibition increased the phosphorylation of BADS99 in PDAC cells, an effect abrogated by NCK. Combined pBADS99-MEK inhibition demonstrated strong synergy in reducing cell viability, enhancing apoptosis, and achieving xenograft stasis in KRAS-mutant PDAC. In conclusion, the inhibition of BADS99 phosphorylation enhances the efficacy of MEK inhibition, and their combined inhibition represents a mechanistically based and potentially effective therapeutic strategy for the treatment of KRAS-mutant PDAC.
靶向治疗 KRAS 突变型胰腺导管腺癌（PDAC）一直是临床肿瘤学的重大挑战。直接靶向 KRAS 已被证明具有挑战性，而抑制 KRAS 效应物由于生存途径的代偿性激活，仅显示出有限的成功。作为 KRAS 驱动的 p44/42 MAPK 和 PI3K/AKT 通路的核心下游效应物，BAD 磷酸化成为有前途的治疗靶标。在此，观察到 pBADS99/BAD 比值与 PDAC 的较高疾病分期和较差总生存率呈正相关。BAD 同源定向修复为 BADS99A 或小分子抑制 BADS99 磷酸化通过促进细胞周期停滞和细胞凋亡，显著降低 PDAC 细胞活力。NCK 还消除了 PDAC 细胞在 3D 培养中形成的预先形成的菌落的生长。此外，通过高通量筛选肿瘤药物文库来鉴定潜在的组合，在携带野生型或突变型-KRAS 的 PDAC 细胞中发现 NCK 和 MEK 抑制剂之间具有很强的协同作用。从机制上讲，突变型 KRAS 和 MEK 抑制均增加了 PDAC 细胞中 BADS99 的磷酸化，这一效应被 NCK 消除。联合 pBADS99-MEK 抑制在降低细胞活力、增强细胞凋亡和实现 KRAS 突变型 PDAC 异种移植物停滞方面显示出强烈的协同作用。总之，抑制 BADS99 磷酸化增强了 MEK 抑制的疗效，它们的联合抑制代表了一种基于机制的、可能有效的治疗 KRAS 突变型 PDAC 的策略。
