This study is led by Prof. Kenneth To (School of Pharmacy, The Chinese University of Hong Kong) and Dr. William Cho (Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong). Drug repurposing refers to the identification of new medicinal indications for existing drugs. It offers the promise of significant cost and time reduction in the development of new medicine as the formulation, pharmacokinetic properties, adverse effects, and post-marketing surveillance safety data have been established for the repurposed drug candidates. The research team has been working on multiple projects aiming at repurposing clinically approved drugs to overcome drug resistance in cancer therapy.
Osimertinib is the only third-generation EGFR tyrosine kinase inhibitors clinically approved for first-line treatment of advanced NSCLC patients harboring EGFR mutations. However, drug resistance severely hinders its clinical efficacy. Acquired MET amplification is an important mechanism causing osimertinib resistance. This study is the first to identify fexofenadine, originally indicated for allergic rhinitis and chronic urticaria, as a putative Met-inhibitor by in silico chemical-protein interactome analysis of known Met inhibitors.
Fexofenadine was verified to inhibit recombinant Met kinase in cell-free assay and phosphorylation of Met and other downstream signaling molecules in osimertinib-resistant NSCLC cell lines. KINOME profiling revealed a similar kinase inhibition profile between fexofenadine and another known Met-inhibitory drug cabozantinib.
The team reported that fexofenadine could effectively enhance the anticancer effect of osimertinib in MET amplified and EGFR T790M mutated NSCLC cell lines. Transcriptome profiling in a cancer cell model revealed that the differentially expressed genes following fexofenadine treatment were enriched in key cancer metastasis-related biological pathways.
Importantly, fexofenadine was also shown to significantly enhance the antitumor efficacy of osimertinib in a drug-refractory NSCLC patient-derived tumor xenograft (PDX) model in mice, without inducing notable adverse effects. As PDX models are known to recapitulate the biology and heterogeneity of human tumor cells, the findings strongly support the potential clinical utility of the repurposed drug for treating NSCLC patients.
Collectively, these novel findings advocate the clinical translation of repurposing fexofenadine to overcome osimertinib resistance in lung cancer therapy.
See the article:
Fexofenadine overcomes osimertinib resistance by inhibiting c-Met in non-small cell lung cancer
https://doi.org/10.1002/mog2.70019
