School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
Biological and Environmental Science and Engineering, Computational Bioscience Research Center, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia.
Proc Natl Acad Sci U S A. 2021 Sep 14;118(37). doi: 10.1073/pnas.2101751118.
The phosphoinositide 3-kinase regulatory subunit p85α is a key regulator of kinase signaling and is frequently mutated in cancers. In the present study, we showed that in addition to weakening the inhibitory interaction between p85α and p110α, a group of driver mutations in the p85α N-terminal SH2 domain activated EGFR, HER2, HER3, c-Met, and IGF-1R in a p110α-independent manner. Cancer cells expressing these mutations exhibited the activation of p110α and the AKT pathway. Interestingly, the activation of EGFR, HER2, and c-Met was attributed to the ability of driver mutations to inhibit HER3 ubiquitination and degradation. The resulting increase in HER3 protein levels promoted its heterodimerization with EGFR, HER2, and c-Met, as well as the allosteric activation of these dimerized partners; however, HER3 silencing abolished this transactivation. Accordingly, inhibitors of either AKT or the HER family reduced the oncogenicity of driver mutations. The combination of these inhibitors resulted in marked synergy. Taken together, our findings provide mechanistic insights and suggest therapeutic strategies targeting a class of recurrent p85α mutations.
磷酸肌醇 3-激酶调节亚基 p85α 是激酶信号的关键调节剂，并且在癌症中经常发生突变。在本研究中，我们表明，除了削弱 p85α 与 p110α 之间的抑制相互作用外，p85α N 端 SH2 结构域中的一组驱动突变以 p110α 非依赖性方式激活了 EGFR、HER2、HER3、c-Met 和 IGF-1R。表达这些突变的癌细胞表现出 p110α 和 AKT 途径的激活。有趣的是，EGFR、HER2 和 c-Met 的激活归因于驱动突变抑制 HER3 泛素化和降解的能力。HER3 蛋白水平的增加促进了其与 EGFR、HER2 和 c-Met 的异二聚化，以及这些二聚化伴侣的别构激活；然而，HER3 沉默消除了这种转激活。因此，AKT 或 HER 家族的抑制剂均可降低驱动突变的致癌性。这些抑制剂的联合使用导致明显的协同作用。总之，我们的研究结果提供了机制见解，并为针对一类复发性 p85α 突变的治疗策略提供了依据。
