Ryo Shinomiya, Yasushi Sato, Takanori Yoshimoto, Tomoyuki Kawaguchi, Akihiro Hirao, Koichi Okamoto, Yutaka Kawano, Masahiro Sogabe, Hiroshi Miyamoto and Tetsuji Takayama : A case of treatmentresistant advanced gastric cancer with FGFR2gene alteration successfully treated with pemigatinib., International Cancer Conference Journal, 13, 240-244, 2024.
(要約)
Comprehensive genome profiling (CGP) is expected to widen the scope of cancer drug options by identifying the genes involved in carcinogenesis. However, a few patients can access recommended treatments following CGP. Herein, we report a case in which pemigatinib, a selective fibroblast growth factor receptor (FGFR) inhibitor, was used as last-line therapy to treat a patient with advanced gastric cancer exhibiting FGFR2 genomic alterations, as determined by CGP testing. The patient (male, 52 years old) was diagnosed with advanced gastric cancer (cStage IV, cT4aN3M1 [LYM], por, HER2 0, microsatellite stable) and received docetaxel + cisplatin + S-1 (7 cycles), irinotecan + ramucirumab (11 cycles), and nivolumab (3 cycles), but experienced progressive disease (PD). Subsequently, FoundationOne Liquid CDx testing was conducted, revealing FGFR2 rearrangement and amplification; however, no clinical trials on genotype-matched therapies for FGFR2 alterations were available. After three cycles of TAS-102, the patient experienced PD and provided consent for the off-label use of pemigatinib. The Cancer Genomics Medical Committee of our hospital approved the self-funded treatment. The patient had markedly decreased CEA and CA19-9 levels after treatment initiation, but experienced PD after five courses. Over the treatment course, grade 1 hyperphosphatemia and onychomadesis were observed. To the best of our knowledge, this is the first reported case of pemigatinib therapy employed in a patient with advanced gastric cancer exhibiting FGFR2 gene alterations. This case could serve as a notable example of tumor-agnostic therapy to broaden treatment options for gastric cancer patients with rare genetic alterations.
The mechanism of resistance to sorafenib in hepatocellular carcinoma (HCC) remains unclear. We analyzed miRNA expression profiles in sorafenib-resistant HCC cell lines (PLC/PRF5-R1/R2) and parental cell lines (PLC/PRF5) to identify the miRNAs responsible for resistance. Drug sensitivity, migration/invasion capabilities, and epithelial-mesenchymal transition (EMT) properties were analyzed by biochemical methods. The clinical relevance of the target genes to survival in HCC patients were assessed using a public database. Four miRNAs were significantly upregulated in PLC/PRF5-R1/-R2 compared with PLC/PRF5. Among them, miR-125b-5p mimic-transfected PLC/PRF5 cells (PLC/PRF5-miR125b) and showed a significantly higher IC50 for sorafenib compared with controls, while the other miRNA mimics did not. PLC/PRF5-miR125b showed lower E-cadherin and higher Snail and vimentin expression-findings similar to those for PLC/PRF5-R2-which suggests the induction of EMT in those cells. PLC/PRF5-miR125b exhibited significantly higher migration and invasion capabilities and induced sorafenib resistance in an in vivo mouse model. Bioinformatic analysis revealed ataxin-1 as a target gene of miR-125b-5p. PLC/PRF5 cells transfected with ataxin-1 siRNA showed a significantly higher IC50, higher migration/invasion capability, higher cancer stem cell population, and an EMT phenotype. Median overall survival in the low-ataxin-1 patient group was significantly shorter than in the high-ataxin-1 group. In conclusion, miR-125b-5p suppressed ataxin-1 and consequently induced Snail-mediated EMT and stemness, leading to a poor prognosis in HCC patients.