The article mainly analyzes the mechanism of action of MYC in inducing resistance to CDK4/6 inhibitors by promoting PRB1 degradation, and suggests that the c-Myc degrading agent a80.2hcl can enhance the therapeutic effect of CDK4/6 inhibitors.
Zhitong Finance App learned that on March 13, Kaituo Pharmaceutical-B (09939) announced that it and its partner recently published a paper in Nature Communications. The article mainly analyzes the mechanism of action of MYC in inducing resistance to CDK4/6 inhibitors by promoting PRB1 degradation, and suggests that the c-Myc degrading agent a80.2HCL can enhance the therapeutic effects of CDK4/6 inhibitors.
CDK4/6 regulates the progression of the early G1 phase of the cell cycle and has a profound impact on the treatment of various solid tumors. CDK4/6 inhibitors have been approved for the treatment of hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer, but their application to other tumors and the underlying drug resistance mechanisms are still unclear. In existing mechanistic studies, loss of normal RB1 function is thought to be a common cause of resistance to CDK4/6 inhibitors. MYC is one of the most widely studied carcinogenic proteins. It can regulate many cellular processes, promote tumor development in many different types of cancer, and cause resistance to treatment.
A80.2HCl is a molecular gum compound independently developed by Pioneer Pharmaceutical. It can degrade c-MYC/GSPT1 and shows nanomolar level antitumor activity in various cancer cells such as bladder cancer/prostate cancer/breast cancer. In breast cancer and bladder xenograft models, a80.2hcl showed good anti-tumor activity when used alone or in combination with the CDK4/6 inhibitor palbociclib. Furthermore, A80.2HCL has been shown to overcome drug resistance induced by Palbocicliband and increase its drug sensitivity.
The study found that:
High expression of myC may cause loss of PRB1 function, leading to resistance to CDK4/6 inhibitors;
High expression of Myc mainly reduces the protein level of PRb1 through proteolytic pathways;
E3 ubiquitin ligase klhl42 interacts with pRb1 to induce pRb1 protease;
As a target of action for MYC transcription factors, KLHL42 can mediate resistance to CDK4/6 inhibitors;
A80.2HCl is a molecular gum compound that degrades Myc;
A80.2hcl enhances the therapeutic effect of CDK4/6 inhibitors.
The researchers concluded that high MYC expression can directly activate the transcription of the E3 ubiquitin ligase KLHL42, promote ubiquitination and degradation of pRb1, leading to a lack of pRb1 protein, thereby inducing resistance to CDK4/6 inhibitors. Kaituo Pharmaceutical's self-developed MYC inhibitor A80.2hcl can degrade Myc at nanomolar levels, restore the activity of PRB1 protein, and reduce the resistance of CDK4/6 inhibitors related to high MYC expression. Furthermore, Cdk4/6 inhibitors were used in combination with a80.2HCl and showed superposition effects on tumor cell-killing activity in both in vitro and in vivo studies.