Scholar - SciOpen

Osimertinib (OSI) therapy, a cornerstone in treating non-small cell lung cancer (NSCLC), has been severely limited by rapidly developing acquired resistance. Inhibition of bypass activation using a combination strategy holds promise in overcoming this resistance. Biguanides, with excellent anti-tumor effects, have recently attracted much attention for this potential. The current study investigated whether novel biguanide compounds developed by our team could overcome OSI resistance and the underlying mechanisms were explored.

Methods

A comprehensive screening assay using OSI-resistant cells identified the optimal combination of biguanide compounds with OSI. Proteomics, co-immunoprecipitation mass spectrometry, RNA sequencing, and homologous recombination assays were used to elucidate the molecular mechanisms underlying combination therapy. NSCLC tumor tissues, especially OSI-resistant tissues, obtained from our clinic were used to assess the correlations between key proteins and OSI resistance.

Results

SMK-010, a highly potent biguanide compound, effectively overcame OSI resistance in vitro and in vivo. Mechanistical studies showed that BMI1/FGFR1 pathway activation is responsible for OSI resistance. Specifically, silencing BMI1 promoted NEDD4-mediated FGFR1 ubiquitination and proteasomal degradation, whereas SMK-010 treatment induced FGFR1 lysosomal degradation. This reduction in FGFR1 levels impaired homologous recombination, increased DNA damage, and surmounted OSI resistance. Analysis of clinical samples revealed overexpression of BMI1 and FGFR1 in NSCLC tissues and represented potential biomarkers for OSI resistance.

Conclusions

These findings highlight the crucial role of the BMI1/FGFR1 axis in OSI resistance and provide a rational basis for the future clinical application of the biguanide, SMK-010, in combination with OSI.

Open Access Review Article Issue

Patient-derived xenograft models: Current status, challenges, and innovations in cancer research

Minqi Liu, Xiaoping Yang

Genes & Diseases 2025, 12(5): 101520

Published: 08 January 2025

Abstract

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Despite advancing therapeutic treatments, cancer remains the leading cause of death worldwide, with most of its patients developing drug resistance and recurrence after initial treatment. Therefore, incorporating preclinical models that mimic human cancer biology and drug responses is essential for improving treatment efficacy and prognosis. Patient-derived xenograft (PDX) models, as a promising and reliable preclinical trial platform, retain key features of the original tumor such as gene expression profiles, histopathological features, drug responses, and molecular signatures more faithfully compared with traditional tumor cell line models and cell line-derived xenograft models. Their significant advantages have been the preferred choice in cancer research, especially demonstrating remarkable potential in drug development, clinical combination therapy, and precision medicine. However, the successful construction and effective application of PDX models still face several challenges. In this review, we summarize the details of constructing PDX models and the drivers affecting their success rates, which will provide some theoretical basis for subsequent model optimization. In the meantime, we delineate the strengths and weaknesses of various mature PDX models and other developing preclinical models, including PDX-derived models, organoids, and genetically engineered models. Moreover, we highlight the challenges of newly developed technologies on the PDX models. Finally, we emphasize the innovative usage of PDX models in a variety of cancer studies and offer insights into their prospects.

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