Liu Qiang's group reveals the mechanism of PI3K/mTOR inhibitor reversing CDK4/6 inhibitor resistance in breast cancer

Since the CDK4/6 inhibitor was approved for marketing in the United States in 2016, it has significantly improved the efficacy and survival of HR+/HER2- advanced breast cancer, and is currently the first-line standard treatment drug recommended globally.

Recently, Liu Qiang's research group from Sun Yat-sen Memorial Hospital of Sun Yat-sen University published a research paper entitled "Overexpressed Cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4/6 inhibitor in breast cancer that can be reversed by PI3K/mTOR Inhibitors" in Science China Life Sciences.

In the early exploration process, the research group found that the expression levels of Cyclin D1 and CDK4 proteins in breast cancer cells after CDK4/6 inhibitor resistance not only did not decrease, but increased significantly, so that tumor proliferation continued to accelerate and was not inhibited by CDK4/6 agent regulation

PI3K/mTOR inhibitors reduce Cyclin D1 and CDK4 expression and reverse CDK4/6 inhibitor resistance

This article is the first to find that the overexpression of Cyclin D1 and CDK4 proteins does not require DNA copy number amplification or mRNA transcription increase, but only the acceleration of the translation process can lead to drug resistance, and the translation acceleration process is just controlled by the PI3K/mTOR pathway, so Select HR+HER2- breast cancers with overexpression of Cyclin D1 and CDK4/6 due to accelerated translation process by biomarkers such as 4E-BP1 protein, and application of PI3K inhibitor can reduce their expression, thus reversing the effect of CDK4/6 inhibitor resistance

Dr.