What is the resistance mechanism of aximinib/asinib

Asciminib is a new type of targeted drug mainly used to treat chronic myelogenous leukemia (CML) and other BCR-ABL related diseases. Different from traditional tyrosine kinase inhibitors (TKIs), Asnib specifically inhibits the T315I mutation of BCR-ABL1 through a unique "new target" mechanism of action, which enables it to show good efficacy in some drug-resistant patients where traditional drugs cannot work. However, although asinib has shown good efficacy in clinical practice, resistance problems still exist, and its resistance mechanism has also become the focus of research.

The resistance mechanism of asinibis mainly related to mutations and other adaptive changes in the BCR-ABL gene. The protein produced by the BCR-ABL gene fusion is a key driver of chronic myelogenous leukemia. Asnib inhibits its kinase activity by binding to the specific domain of this fusion protein. However, mutations in the BCR-ABL fusion gene may affect the effectiveness of the drug. For example, the T315I mutation is the most well-known drug-resistant mutation. This mutation will lead to changes in the drug binding site, thereby reducing the binding affinity between Asnib and BCR-ABL, resulting in a weakened therapeutic effect.

In addition toT315I mutation, other mutations such as F359V and E255K have also been found to be associated withasinibresistance. These mutations may lead to changes in the three-dimensional structure of the BCR-ABL protein, making the drug unable to effectively inhibit its kinase activity. As treatment progresses, cancer cells adapt to the inhibitory effects of the drug through these gene mutations and protein changes, resulting in the gradual decrease in the efficacy of Asnib.

In addition to genetic mutations, intracellular drug elimination mechanisms may also be involved in asinib resistance. For example, tumor cells may accelerate the elimination of asinib by overexpressing drug efflux proteins (such asP-glycoprotein), reducing the effective concentration of the drug, thereby leading to drug resistance.

Reference materials:https://www.novartis.com/our-products/pipeline/asciminib