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  • After the successful development of molecular targeted

    2022-05-27

    After the successful development of molecular targeted drugs in lung adenocarcinoma, substantial efforts have been made to provide similar targeted drugs in lung squamous-cell carcinoma. Because FGFR gene alteration is the most frequent occurrence in squamous-cell carcinoma, targeted therapies for FGFR including ponatinib, AZD4547, and BJG003 are being evaluated.4, 5, 6 Preliminary clinical data found that only a small subset of enrolled patients have disease that responds to these FGFR1 TKIs. One potential explanation may be the improper use of FGFR amplification as a patient selection biomarker. As identified in our previous study, FGFR1 mRNA or protein expression, but not gene copy number, better predicts FGFR TKI sensitivity across all lung cancer cell line studies. These previous data suggested the need for better biomarkers to predict tumor sensitivity to targeted drugs. Currently, efforts to identify patients who are likely to experience anticancer treatment failure are ongoing, and evaluations of miRNA dysregulation to support this endeavor have been reported.24, 25 Lim et al further used RNA sequencing to comprehensively analyze the miRNA difference Amphotericin B between primary and refractory pediatric acute myeloid leukemia samples and found 3 candidate miRNAs, indicating that they may be associated with treatment resistance. In this study, we first developed a miRNA panel to predict sensitivity to FGFR inhibitors through comprehensive analysis of miRNA expression in 34 thoracic cancer cell lines, which showed consistent results both in ponatinib and AZD4547 cell line cohorts. While this work was performed exclusively in cell lines, further studies on tumor tissue specimens from patients must be performed to validate the potential role for this miRNA panel. However, liquid biopsy shows an obvious advantage compared to tumor biopsy in the areas of efficacy surveillance and relapse monitoring because liquid biopsy is nearly noninvasive. Thus, our miRNA panel might be better than FGFR1 mRNA or protein expression if this miRNA panel in circulating miRNA was identified as a reliable predictive factor for screening patients for FGFR1 inhibitor—which is our next research step in the near future. In addition, the 34 cell lines included into this study contained different histologic subtypes such as adenocarcinoma, squamous-cell, large-cell, and small-cell cell lines without known oncogenic mutations, which might not represent the whole lung cancer population. However, because FGFR1 inhibitors are rarely effective in patients with EGFR/ALK/ROS1 mutation, investigation of the biomarker for FGFR1 inhibitor in oncogenic driver pan-negative cell lines will be helpful in identifying a potential one with clinical applications. Additionally, because let-7c was the most robust miRNA in the univariate analysis to predict sensitivity to ponatinib, we further investigated the correlation between let-7c and FGFR1 mRNA. We found that let-7c silencing was significantly associated with decreased expression of FGFR1, suggesting that let-7c predicts, but also participates in, regulation of FGFR1 mRNA levels and thereby sensitivity to ponatinib. It has been reported that let-7 has been demonstrated to be a direct regulator of RAS and HMGA2 expression in human cells through binding sequences in their 3′ untranslated regions. However, the detailed mechanism of let-7c and correlated changes in FGFR1 mRNA is still unknown and warrants further investigation.
    Conclusion
    Disclosure
    Acknowledgments
    Fibroblast growth factor receptors (s) are activated in a subset of urothelial cell carcinoma (UCC), most commonly by mutation or overexpression of . Clinical trials with FGFR inhibitors (FGFRi) are currently ongoing in UCC. Initial results with BGJ398 showed encouraging response rates , though information on the durability of these responses is currently lacking. Akin to other molecularly-targeted therapies, resistance is likely to be a major concern. Resistance to FGFR inhibition was observed (A, Supplementary materials and methods): the - translocated cell line RT112 responded initially, but cells quickly adapted to AZD4547, an inhibitor of FGFR1, FGFR2, and FGFR3 (weaker activity against FGFR4). Resistance to targeted therapies often develops through feedback activation of additional signaling pathways: one such example is synergy between FGFRi with inhibitors of epidermal growth factor receptor (EGFR) . Feedback mechanisms that render cells insensitive to kinase inhibition often occur through activation of other kinases. We screened a short hairpin RNA (shRNA) library targeting all 518 human kinases and 17 additional kinase-related genes to find genes whose inhibition enhances the sensitivity to FGFRi AZD4547 in mutant UCC (B). RT112 cells were infected with a lentiviral library containing some 5000 shRNAs and cultured in the absence or presence of AZD4547 for 14 d. Cells were then harvested, DNA was isolated, and the relative abundance of shRNA vectors was measured by deep sequencing. The read counts were normalized and analyzed with DESeq2 () to identify shRNAs and their corresponding target genes that show significant depletion in the presence of AZD4547 (Supplementary Tables 1 and 2). We observed multiple components of the PI3K signaling pathway including the catalytic component , the regulatory subunit , and the downstream target (C). In addition, we found for which synergy with FGFR inhibition has been described . Because of the presence of several components of the PI3K pathway, we decided to focus our validation on the central node, the catalytic subunit of PI3K, . Three different shRNAs targeting were significantly depleted in the drug-treated group compared with the control. This suggested that suppression of synergizes with FGFRi in mutant bladder cancer. To validate this finding, we infected RT112 cells with each of these three shRNAs targeting and treated with or without Amphotericin B AZD4547 for 2 wk. All three shRNAs against induce efficient knockdown of PIK3CA protein expression as determined by western blot analysis (D). Parental RT112 cells did not significantly respond to FGFR inhibition or suppression alone, but knockdown of strongly enhanced the response to the FGFRi AZD4547 (E).