New development of inhibitors targeting the PI3K/AKT/mTOR pathway in personalized treatment of non-small-cell lung cancer.

Lung cancer is the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) is the most common pathological type of lung cancer, divided into squamous cell carcinoma and adenocarcinoma. Despite better techniques of surgery and improvement in adjuvant and neoadjuvant therapy, the median survival of advanced NSCLC is only 8-10 months. With increased understanding of molecular alternations in NSCLC, considerable efforts have focused on the development of personalized molecular-targeted therapies. The PI3K/AKT/mTOR pathway regulates tumor development, growth, and proliferation of NSCLC. Various novel inhibitors targeting this pathway have been identified in preclinical studies or clinical trials. Some genetic alternations may be considered sensitive or resistant biomarkers to these inhibitors. Sometimes, upregulation of RTK and the downstream PI3K pathway or upregulation of the ERK pathway by compensatory feedback reactivation in response to these inhibitors also lead to drug resistance. Therefore, combination therapy of these inhibitors and other targeted inhibitors such as EGFR-TKI or MEK inhibitors according to genetic status and categories of inhibitors is required to enhance the efficacy of these inhibitors. Here, we reviewed the genetic status of the PI3K/AKT/mTOR pathway in NSCLC and the novel inhibitors targeting this pathway in preclinical or clinical studies, exploring the possible genetic alternations related to different inhibitors and the means to enhance the antitumor effect in NSCLC.