Discovery of combination therapy for KRAS mutant cancer

背景资料。靶向治疗药物，包括MEK和ERK激酶抑制剂，对具有KRAS突变的实体肿瘤显示出非常有限的疗效。鉴定能够协同杀死KRAS突变癌细胞的药物组合可能会带来新的治疗方式。目的。在这个项目中，我们的目标是进行高通量药物组合筛选，以寻找在体外对KRAS突变癌细胞表现出较强选择性的协同组合。我们的目标是验证屏幕上的热门歌曲，并评估它们的翻译潜力。成就。我们已经完成了初步筛选，并确定了一种在KRAS突变癌细胞系中具有协同细胞杀伤作用的候选药物组合。我们已经在体外确定了药物协同作用的机制。我们发现，KRAS突变的胰腺癌细胞系中的一部分对这种组合敏感。描述这一发现的手稿已经提交出版。

BACKGROUND. Targeted therapeutic agents, including MEK and ERK kinase inhibitors, haves shown very limited efficacy against solid tumors with KRAS mutations. The identification of drug combinations that can synergistically kill KRAS mutant cancer cells could lead to new therapeutic modality. PURPOSE. In this project we aim to carry out a high-throughput drug combination screen to identify synergistic combinations that show strong selectivity in KRAS mutant cancer cells in vitro. We aim to validate hits from the screen and evaluate their translational potential. ACCOMPLISHMENT. We have completed the primary screen and have identified a candidate drug combination with synergistic cell killing effect in KRAS mutant cancer cell lines. We have identified the mechanism of drug synergy in vitro. We showed that a fraction of KRAS mutant pancreatic cancer cell lines are sensitive to this combination. A manuscript describing this finding has been submitted for publication.