Research Progress on Drugs Targeting PIK3CA Mutations

PI3K/AKT/mTOR通路是细胞内一个重要的信号传导通路，参与调控细胞的增殖、生长、代谢和存活等多种生物学过程，在多种癌症中发生突变或扩增，包括乳腺癌、胃癌、卵巢癌等。该信号通路在癌细胞存活、血管生成和转移中起重要作用。PI3Kα是该通路中一种关键的脂质激酶，具有催化和抑制两个亚基，其中PIK3CA是编码p110α催化亚基的基因，是一种在多种亚型乳腺癌中高度突变的癌症蛋白，且PI3Kα信号转导失调通常与肿瘤发生和耐药性有关，因此，靶向PIK3CA突变的药物研发是目前乳腺癌精准治疗的热门方向。针对PI3K的选择性抑制剂已经被成功开发，PI3Kα特异性抑制剂阿培利司(Alpelisib)已被FDA批准作为PIK3CA突变乳腺癌的治疗药物。然而由于毒性问题未能有效解决，该药物的应用仍有限制。在这篇综述中，我们将总结PIK3CA突变导致乳腺癌耐药机制及靶向PIK3CA突变的药物研发的安全性问题和最新进展，以期对PIK3CA突变患者提供更有效的个体化治疗。The PI3K/AKT/mTOR pathway is a critical intracellular signaling cascade that regulates diverse biological processes, including cell proliferation, growth, metabolism, and survival. This pathway undergoes mutations or amplifications in various cancers, such as breast cancer, gastric cancer, and ovarian cancer. It plays a pivotal role in the survival, angiogenesis, and metastasis of cancer cells. PI3Kα serves as a key lipid kinase within this pathway, consisting of two subunits: catalytic and regulatory. Notably, PIK3CA is the gene encoding the catalytic subunit p110α, which is frequently mutated in multiple subtypes of breast cancer. Dysregulation of PI3Kα signaling is often associated with tumorigenesis and drug resistance. Consequently, the development of drugs targeting PIK3CA mutations has become a prominent focus in the precision treatment of breast cancer. Selective inhibitors targeting PI3K have been successfully developed, and the PI3Kα-specific inhibitor Alpelisib has been approved by the FDA for the treatment of PIK3CA-mutated breast cancer. However, the clinical application of these drugs remains limited due to unresolved toxicity issues. In this review, we summarize the mechanisms underlying drug resistance in PIK3CA-mutated breast cancer, as well as the safety concerns and recent advancements in the development of PIK3CA-targeted therapies. Our aim is to provide insights into more effective personalized treatment strategies for patients harboring PIK3CA mutations.