What are the manifestations of resistance to mobosetinib/mobosetinib?

Mobocertinib brings new therapeutic hope to patients with non-small cell lung cancer with EGFR exon20 insertion mutations. However, similar to other targeted therapies, drug resistance is still an important challenge that must be faced in clinical practice. Mobosetinib resistance usually gradually appears after several months or even a year of treatment, with complex manifestations and large individual differences. The most common manifestations of resistance are re-increase in tumor size, recurrence of the primary tumor, or the emergence of new metastatic lesions, which can usually be detected by imaging evaluation. Patients may also reappear with clinical symptoms, such as cough, shortness of breath, chest pain, rapid weight loss, etc. These signals indicate that they may have lost sensitivity to current treatments.

From a molecular level, the resistance mechanism of mobosetinib has not been fully understood, but studies have pointed out the possibility of secondary mutations, such as re-mutation of the EGFR gene site, or activation of bypass signaling pathways such as MET amplification, HER2 mutations, BRAF mutations, etc. These molecular changes may enable cancer cells to escape signaling chains inhibited by mobosetinib, leading to drug resistance. The resistance of some patients may also involve EMT (epithelial-to-mesenchymal transition), changes in the tumor microenvironment, or cell phenotype transformation, resulting in small cell lung cancer-like characteristics. These complex mechanisms make treatment more difficult.

Identifying resistance to mobosetinib must rely on dynamic molecular detection methods, such as ctDNA liquid biopsy or tissue biopsy, to help determine the specific resistance mechanism and provide direction for subsequent treatment. Once drug resistance is confirmed, clinical trials may include switching to other targeted drugs, combination chemotherapy, immunotherapy, or entering clinical trials. In addition, some new-generation EGFR exon20-targeted drugs are being developed and are expected to break through the current treatment bottleneck.

Reference materials:https://en.wikipedia.org/wiki/Mobocertinib