47P - Integration of miRNA profiles and p53 mutations as biomarkers for predicting sensitivity and resistance to FGFR inhibitor CPL110 in cancer therapy

Background

Fibroblast Growth Factor Receptors (FGFRs) play a crucial role in various types of cancer, yet their efficacy as therapeutic targets remains uncertain due to a significant portion of patients exhibiting resistance to FGFR inhibitors. Understanding the mechanisms behind this resistance necessitates an examination of both genetic and epigenetic factors. In this study, we investigated microRNA (miRNA) expression patterns and p53 mutation status in cancer cell lines with diverse genetic backgrounds and varying sensitivity to the novel FGFR inhibitor, CPL110.

Methods

To identify potential biomarkers, we assessed the correlation between drug sensitivity (IC50) and molecular characteristics in a panel of 160 cell lines from 27 cancer types. Using CPL110-sensitive (WT) and -resistant (R) cancer cell lines from lung, gastric, and urinary tract cancers, we analysed genetic profiles and miRNA expression with the Nanostring platform, covering 827 human miRNAs. All analyses were performed using R software.

Results

Significant differences in miRNA expression were identified in the wild-type cell lines (FDR p-value ≤ 0.05, treated vs. non-treated cells). The greatest expression diversity was observed in urinary tract cancers. In the UM-UC14 cell line, three miRNAs (hsa-miR-374a, hsa-miR-21-5p, hsa-miR-19b-3p) were upregulated, while two miRNAs (hsa-miR-4454, hsa-miR-7975) were downregulated, findings also observed in the RT112 cell line. For the H1581 lung cancer cell line, only hsa-miR-1246 was upregulated. A comprehensive database search (TargetScanHuman 8.0, miRPathDB 2.0, miRDB, miRTarBase) identified that these miRNAs are strongly associated with the regulation of FGFR-related pathways. This data underscores the associations between miRNA expression, p53 mutations, chromosome 12 amplification and response to CPL110, highlighting the complexity of FGFR signalling pathways in cancer biology and suggesting these factors as potential biomarkers for response to FGFR inhibitors.

Conclusions

Our results indicate distinct miRNA signatures associated with treatment response and underscore the role of p53 mutations in modulating sensitivity and resistance to FGFR inhibitor therapy.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Agency for Medical Research; Celon Pharma S.A.

Disclosure

M.M. Skupinska, M. Walczak, A. Mikolajczyk: Financial Interests, Personal, Full or part-time Employment: Celon Pharma S.A. M. Wieczorek: Financial Interests, Personal, Ownership Interest: Celon Pharma S.A. D. Popiel: Financial Interests, Personal, Principal Investigator: Celon Pharma S.A.