Background: Oncogenic KRAS mutations are nearly ubiquitous in pancreatic ductal adenocarcinoma (PDAC), yet therapeutic attempts to target KRAS, as well as downstream MAPK pathway effectors, have shown limited clinical success. While KRAS canonically drives MAPK signaling via RAF-MEK-ERK, it is also known to play a role in PI3K-AKT signaling.Methods: Our therapeutic study targeted the PI3K pathway with the drug Omipalisib (p110α/β/δ/γ and mTORC1/2 inhibitor) in combination with two different MAPK pathway inhibitors: Trametinib (MEK1/2 inhibitor) or SHP099-HCL (SHP099; SHP2 inhibitor). Western blot analysis demonstrated that the application of Trametinib or SHP099 alone selectively blocked ERK phosphorylation (pERK) but failed to suppress phosphorylated AKT (pAKT). Conversely, Omipalisib alone successfully inhibited pAKT but failed to suppress pERK. Therefore, we hypothesized that a combination therapeutic comprised of Omipalisib with either Trametinib or SHP099 would inhibit two prominent mitogenic pathways, MAPK and PI3K-AKT, and effectively suppress PDAC growth.Results: In vitro studies demonstrated that, in several cell lines, both Omipalisib/Trametinib and Omipalisib/SHP099 combination therapeutic strategies were more effective than treatment with each drug individually at reducing proliferation, colony formation, and cell migration compared to vehicle controls. In vivo oral administration of combined Omipalisib/Trametinib treatment was significantly more effective than Omipalisib/SHP099 in reducing implanted tumor growth, and the Omipalisib/Trametinib treatment more effectively reduced tumor progression and prolonged survival in an aggressive genetically engineered mouse model of PDAC than either Omipalisib or Trametinib alone.Conclusions: Altogether, our data support a rationale for a dual treatment strategy targeting both PI3K and MAPK pathways in pancreatic cancers.
背景：致癌性KRAS突变在胰腺导管腺癌（PDAC）中几乎普遍存在，然而针对KRAS及其下游MAPK通路效应器的治疗尝试临床效果有限。尽管KRAS主要通过RAF-MEK-ERK驱动MAPK信号传导，但已知其在PI3K-AKT信号通路中也发挥作用。 方法：本研究采用药物奥米帕利西（p110α/β/δ/γ及mTORC1/2抑制剂）靶向PI3K通路，并联合两种不同的MAPK通路抑制剂：曲美替尼（MEK1/2抑制剂）或SHP099-HCL（SHP099；SHP2抑制剂）。蛋白质印迹分析表明，单独应用曲美替尼或SHP099能选择性阻断ERK磷酸化（pERK），但无法抑制磷酸化AKT（pAKT）。相反，单独使用奥米帕利西能有效抑制pAKT，但无法抑制pERK。因此我们提出假设：奥米帕利西联合曲美替尼或SHP099的组合疗法将同时抑制MAPK和PI3K-AKT这两条重要的促有丝分裂通路，从而有效抑制PDAC生长。 结果：体外研究表明，在多种细胞系中，与溶剂对照组相比，奥米帕利西/曲美替尼和奥米帕利西/SHP099两种联合治疗策略在抑制细胞增殖、集落形成和细胞迁移方面均比单一药物治疗更有效。体内实验显示，口服奥米帕利西/曲美替尼联合治疗在抑制移植瘤生长方面显著优于奥米帕利西/SHP099组合；在侵袭性PDAC基因工程小鼠模型中，奥米帕利西/曲美替尼联合治疗比单用奥米帕利西或曲美替尼更能有效延缓肿瘤进展并延长生存期。 结论：综合而言，我们的研究数据为胰腺癌中同时靶向PI3K和MAPK通路的双重治疗策略提供了理论依据。
Combined Omipalisib and MAPK Inhibition Suppress PDAC Growth
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