Discovery of combination therapy for KRAS mutant cancer

背景。包括MEK和ERK激酶抑制剂在内的靶向治疗药物对KRAS突变实体瘤的疗效非常有限。能够协同杀死KRAS突变癌细胞的药物组合的鉴定可能会导致新的治疗方式。目的。在本项目中，我们的目标是进行高通量药物联合筛选，以确定体外KRAS突变癌细胞中表现出强选择性的协同组合。我们的目标是验证屏幕上的点击并评估它们的翻译潜力。的成就。我们已经完成了初步筛选，并确定了一种对KRAS突变癌细胞具有协同杀伤作用的候选药物组合。我们已经确定了体外药物协同作用的机制。我们发现一小部分KRAS突变胰腺癌细胞系对这种组合敏感。描述这一发现的手稿已提交出版。

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.