Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
Semin Cancer Biol. 2019 Dec;59:3-22. doi: 10.1016/j.semcancer.2019.03.006. Epub 2019 Mar 31.
The phosphoinositide 3-kinase (PI3K) pathway, one of the most commonly activated signaling pathways in human cancers, plays a crucial role in the regulation of cell proliferation, differentiation, and survival. This pathway is usually activated by receptor tyrosine kinases (RTKs), whose constitutive and aberrant activation is via gain-of-function mutations, chromosomal rearrangement, gene amplification and autocrine. Blockage of PI3K pathway by targeted therapy on RTKs with tyrosine kinases inhibitors (TKIs) and monoclonal antibodies (mAbs) has achieved great progress in past decades; however, there still remain big challenges during their clinical application. In this review, we provide an overview about the most frequently encountered alterations in RTKs and focus on current therapeutic agents developed to counteract their aberrant functions, accompanied with discussions of two major challenges to the RTKs-targeted therapy in cancer - resistance and toxicity.
磷酸肌醇 3-激酶（PI3K）途径是人类癌症中最常被激活的信号通路之一，在细胞增殖、分化和存活的调节中起着关键作用。该途径通常通过受体酪氨酸激酶（RTKs）激活，其组成性和异常激活是通过获得功能突变、染色体重排、基因扩增和自分泌。过去几十年中，通过针对 RTKs 的酪氨酸激酶抑制剂（TKIs）和单克隆抗体（mAbs）的靶向治疗阻断 PI3K 途径取得了重大进展；然而，在其临床应用中仍存在巨大挑战。在这篇综述中，我们概述了 RTKs 中最常见的改变，并重点介绍了目前开发的用于对抗其异常功能的治疗药物，同时讨论了 RTKs 靶向治疗癌症的两个主要挑战——耐药性和毒性。
