磷酸肌醇依赖性激酶-1（PDK1）是AGC家族激酶的主激酶，它在调节癌细胞增殖、存活和代谢中起着重要作用。除了以PI3K依赖的方式在细胞膜上对AKT进行磷酸化/活化外，PDK1在许多其他AGC激酶上也表现出固有的活性，从而促进肿瘤的发展。在后一种情况下，PDK1蛋白水平占据着主导地位来调控其活性。我们先前的研究报道了非典型MAPK4能够以PI3K独立的方式促进AKT的活化和肿瘤生长。在这里，我们使用三阴性乳腺癌（TNBC）细胞模型证明，MAPK4还可以增强PDK1的蛋白合成，并通过磷酸化/活化PDK1底物来超越AKT的功能。这一新的MAPK4-PDK1轴单独缺乏强烈的促进肿瘤活性，但与我们之前报道的MAPK4-AKT轴合作来促进肿瘤生长。除了增加对PI3K阻断的抵抗力，MAPK4还促使癌细胞增加对更为严格的PI3K和PDK1联合阻断的耐药性，这是一种最近提出的治疗策略。目前还没有针对MAPK4的抑制剂来治疗MAPK4高表达的癌症。基于MAPK4-AKT和MAPK4-PDK1轴在促进癌症中的共同作用，我们预测并证实共靶向AKT和PDK1可以有效抑制MAPK4诱导的癌细胞生长，这可能是一种治疗MAPK4高表达癌症的潜在策略。版权所有：© 2023年韩等人。本文是根据知识共享署名许可协议发布的开放获取文章，并允许在任何媒介中自由使用、分发和再制作，前提是原始作者和来源得到了官方认可。

Phosphoinositide-dependent kinase-1 (PDK1) is a master kinase of the protein A, G, and C (AGC) family kinases that play important roles in regulating cancer cell proliferation, survival, and metabolism. Besides phosphorylating/activating AKT at the cell membrane in a PI3K-dependent manner, PDK1 also exhibits constitutive activity on many other AGC kinases for tumor-promoting activity. In the latter case, PDK1 protein levels dominate its activity. We previously reported that MAPK4, an atypical MAPK, can PI3K-independently promote AKT activation and tumor growth. Here, using triple-negative breast cancer (TNBC) cell models, we demonstrate that MAPK4 can also enhance PDK1 protein synthesis, thus phosphorylate/activate PDK1 substrates beyond AKT. This new MAPK4-PDK1 axis alone lacks vigorous tumor-promoting activity but cooperates with our previously reported MAPK4-AKT axis to promote tumor growth. Besides enhancing resistance to PI3K blockade, MAPK4 also promotes cancer cell resistance to the more stringent PI3K and PDK1 co-blockade, a recently proposed therapeutic strategy. Currently, there is no MAPK4 inhibitor to treat MAPK4-high cancers. Based on the concerted action of MAPK4-AKT and MAPK4-PDK1 axis in promoting cancer, we predict and confirm that co-targeting AKT and PDK1 effectively represses MAPK4-induced cancer cell growth, suggesting a potential therapeutic strategy to treat MAPK4-high cancers.Copyright: © 2023 Han et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.