Analysis of possible resistance to serputinib/serpatinib (Ruitu)

Selpercatinib/Selpercatinib has shown significant efficacy in the treatment of non-small cell lung cancer (NSCLC), thyroid cancer and other cancers related to RET gene mutations, but like many targeted therapy drugs, it also has drug resistance problems. Drug resistance means that after tumor cells initially respond to drug treatment, they become no longer sensitive to the drug over time, resulting in reduced or even ineffective treatment effect.

The resistance mechanism of seputinib may be related to the following factors:

1. Further development of mutations: During long-term treatment, tumor cells may develop new mutations, causing the drug to be unable to effectively inhibitRET kinase. For example, the RET gene itself may undergo secondary mutations, such as RET TKI mutations. These mutations can change the target of seputinib, making it unable to bind to RET tyrosine kinase, resulting in drug failure.

2. Activating other signaling pathways: Tumor cells may bypass the inhibitory effect of seputinib through the activation of other genes or signaling pathways. For example, some tumor cells may maintain their proliferation and growth through activation of the EGFR or MET pathways, even if the RET signaling pathway is inhibited. This type of drug resistance often involves tumor cell adaptive changes and the search for new growth mechanisms.

3. Increase in drug efflux pumps: Similar to other targeted drugs, seputinib may be excreted out of the cells through drug efflux pumps inside and outside tumor cells, reducing the effective concentration of the drug. Tumor cells clear seputinib by increasing the activity of drug efflux pumps, thereby reducing drug accumulation in tumor tissues and leading to the occurrence of drug resistance.

4. Changes in the tumor microenvironment: As treatment progresses, the tumor microenvironment may change, and factors such as immune cells, vasculature, and stromal cells in the tumor may affect the distribution and effect of the drug. Some tumor cells may have acquired stronger drug resistance due to changes in the microenvironment, making the therapeutic effect of seputinib no longer durable.

Reference:https://en.wikipedia.org/wiki/Selpercatinib