Pemetinib resistance mechanism

Pemetinib is an oral tyrosine kinase inhibitor targeting fibroblast growth factor receptor2 (FGFR2). It is mainly used to treat patients with cholangiocarcinoma who have FGFR2 gene fusion or rearrangement. This drug effectively blocks the growth signaling of tumor cells by targeting the activation of the FGFR2 signaling pathway, thereby inhibiting the proliferation of cancer cells. However, although pemetinib has shown certain clinical efficacy, the development of acquired resistance has become an important factor limiting its clinical benefit.

In patients with cholangiocarcinoma, FGFR2 gene variation is one of the common oncogenic drivers. This mutation leads to abnormal activation of the FGFR2 signaling pathway, thereby promoting the proliferation and invasion of tumor cells. Pemetinib, as an FGFR inhibitor, can exert anti-cancer effects against this mutation. However, with the passage of treatment, some patients will develop resistance to pemetinib. The generation of this drug resistance is often related to multiple mechanisms in tumor cells.

In terms of experimental design, the researchers analyzed82casesFGFR2variant cholangiocarcinoma patients who receivedFGFRSamples from disease progression after treatment with >FGFR inhibitors revealed that the development of acquired resistance is often accompanied by secondary FGFR2kinase domain mutations. These mutations allow tumor cells to bypass the inhibitory effects of pemetinib and continue to grow and spread.

The study results showed that 60% of patients had one or more secondary kinase domain mutations of FGFR2 detected after acquired drug resistance. Among them, N550molecular brake mutation and V565gatekeeper mutation are the two most common mutation types, accounting for 63% and 47% of the total mutations respectively. These mutations change the structure and function of the FGFR2kinase domain, making pemetinib unable to effectively inhibit the activation of the FGFR2 signaling pathway.

Further functional studies have shown that differentFGFR inhibitors have significant effects onFGFR2 mutations exhibit unique activity profiles. For example, disruption of the covalently bound cysteine u200bu200bresidue (FGFR2 C492) of fortibatinib, an irreversible inhibitor of FGFR, is rarely seen in drug-resistant patients. This suggests that the FGFR2 C492 mutation is insensitive to inhibition by fortibatinib but has reduced signaling activity, which may explain the low frequency of this mutation in resistant patients.

In summary, the resistance mechanism of pemetinib mainly involves secondary FGFR2kinase domain mutations. These mutations allow tumor cells to bypass the inhibitory effects of pemetinib and continue to grow and spread. Therefore, the development of combinatorial strategies and next-generation FGFR inhibitors targeting the full spectrum of FGFR2resistance mutations will be critical. By combining other targeted drugs, immunotherapy drugs or chemotherapy drugs, the anti-cancer effect of pemetinib can be enhanced and the patient's survival period can be prolonged. At the same time, in-depth research on the mechanisms of drug resistance will also help to develop more effective treatment strategies and provide better treatment options for patients with cholangiocarcinoma.

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Reference link: https://pubmed.ncbi.nlm.nih.gov/37843855/