👤 Hiroki Shimura

Muscle-invasive bladder cancer (MIBC) is an aggressive malignancy with high recurrence and poor survival, accounting for the majority of bladder cancer-related deaths. A subset of MIBC harbors FGFR1 amplification or overexpression, associated with increased proliferation and poor prognosis. Although the pan-FGFR inhibitor erdafitinib has demonstrated clinical benefit in patients with FGFR3/FGFR2 alterations, primarily in non-MIBC, its efficacy is limited by resistance and toxicity. Moreover, its effectiveness in FGFR1-driven MIBC remains unclear. To address this gap, we investigated erdafitinib response and resistance mechanisms in JMSU1 cells, a model of FGFR1-amplified MIBC. While erdafitinib initially suppressed tumor growth, prolonged treatment led to resistance, characterized by persistent activation of ERK, AKT, and STAT1 signaling pathways. Mechanistic studies identified MET activation, driven by MET gene amplification, as a key driver of resistance. Notably, exogenous hepatocyte growth factor (HGF) not only induced resistance but also accelerated the emergence of MET-amplified, HGF-independent subpopulations under drug pressure. We also identified SHP2 as a critical mediator of FGFR1-driven ERK activation in parental cells. In resistant cells, MET activation enhanced SHP2-ERK signaling through the adaptor protein GAB1, reinforcing the resistant phenotype. Combined inhibition of FGFR1 and MET significantly suppressed tumor growth in resistant cells. These findings establish MET amplification and GAB1-SHP2 signaling as central mediators of erdafitinib resistance in FGFR1-amplified MIBC and support dual FGFR1/MET targeting as a promising therapeutic strategy. Show less

Futibatinib is the only covalent inhibitor of FGFR1-4 to gain regulatory approval in oncology. In this article, we present genomic analyses of tissue biopsies and circulating tumor DNA (ctDNA) from patients with 1 of nearly 20 tumor types treated with futibatinib in the phase I/II FOENIX study. Eligible patients included those with ctDNA samples collected per protocol at baseline and/or progression on futibatinib in the phase Ib portion of the study for FGF/FGFR-altered advanced solid tumors or the phase II portion of the study for FGFR2 fusion/rearrangement-positive cholangiocarcinoma. Assessments included analytical concordance between tumor and ctDNA analyses for detection of FGFR alterations, association of ctDNA-detected co-occurring genomic alterations with response to futibatinib, and determination of patterns of acquired resistance following progression on futibatinib. Among 300 patients treated with futibatinib, 226 were eligible for this analysis, including 139 (62%) with cholangiocarcinoma. Among patients with known FGFR2 fusions/rearrangements, FGFR1 fusions, FGFR3 fusions, or FGFR2 amplifications per tissue analysis, detection rates in ctDNA for these aberrations were 84%, 0%, 11%, and 59%, respectively. Objective response rates on futibatinib were not significantly different between patients with TP53-altered versus -unaltered solid tumors; progression-free survival was reduced in patients with CDKN2B-altered versus -unaltered cholangiocarcinoma (median 4.8 versus 11.0 months; P = 0.03). Acquired resistance to futibatinib was frequently polyclonal and driven by an array of mutations within the relevant FGFR kinase domain, predominantly V565L, V565F, and N550K variants. In this largest and most systematic analysis of acquired resistance to an FGFR inhibitor from prospective clinical trials, emergence of secondary FGFR2 kinase domain mutations was observed in most patients receiving clinical benefit to futibatinib. ctDNA analysis shows clinically relevant potential as a noninvasive method for assessing genomic profiles, identifying patients who may benefit from FGFR inhibitor treatment, and exploring acquired resistance mechanisms. Show less

Futibatinib, a covalently-binding inhibitor of fibroblast growth factor receptor (FGFR)1-4 gained approval for the treatment of refractory, advanced intrahepatic cholangiocarcinoma (iCCA) harboring an FGFR2 fusion/other rearrangement. An integrated analysis was performed to evaluate safety and provide guidance on the management of futibatinib-associated adverse events (AEs) in patients with unresectable/metastatic tumors, including iCCA. Data from three global phase I or II studies of futibatinib (NCT02052778; JapicCTI-142552) were pooled. AEs were graded per NCI CTCAE v4.03, where applicable. Safety was analyzed for patients receiving any futibatinib starting dose (overall population) and in those receiving the approved starting dose of 20 mg once every day. In total, 469 patients with one of 33 known tumor types were analyzed, including 318 patients who received futibatinib 20 mg every day. AEs of clinical interest (AECI; any grade/grade ≥3) in the overall population included hyperphosphatemia (82%/19%), nail disorders (27%/1%), hepatic AEs (27%/11%), stomatitis (19%/3%), palmar-plantar erythrodysesthesia syndrome (PPES; 13%/3%), rash (9%/0%), retinal disorders (8%/0%), and cataract (4%/1%). Median time to onset of grade ≥3 AECIs ranged from 9 days (hyperphosphatemia) to 125 days (cataract). Grade ≥3 hyperphosphatemia, hepatic AEs, PPES, and nail disorders resolved to grade ≤2 within a median of 7, 7, 8, and 28 days, respectively. Discontinuations due to treatment-related AEs were rare (2%), and no treatment-related deaths occurred. AE management included phosphate-lowering medication and dose adjustments. Futibatinib showed a consistent and manageable safety profile across patients with various tumor types. AECIs were mostly reversible with appropriate clinical management. Show less

The detoxification of ammonia to urea requires a functional hepatic urea cycle, which consists of six enzymes and two mitochondrial membrane transporters. The initial step of the urea cycle is catalyzed by carbamyl phosphate synthetase 1 (CPS1). CPS1 deficiency (CPS1D) is a rare autosomal recessive disorder. Show less

Expression of intragenic exon rearrangements (IERs) has reportedly been detected in both normal and cancer cells. However, there have been few reports of occurrence of these rearrangements specific to neoplasms including malignant lymphoma. In this study, we detected IERs of ten genes (NBPF8, SOBP, AUTS2, RAB21, SPATA13, ABCC4, WDR7, PHLPP1, NFATC1 and MAGED1) in non-Hodgkin B cell lymphoma (B-NHL) cell line KPUM-UH1 using a high-resolution single nucleotide polymorphism array and reverse transcription polymerase chain reaction using reversely directed divergent primers within exons involved in genomic intragenic gains followed by sequencing analysis. Among them, the IERs involved in SOBP (6q21) exon 2 and 3 and AUTS2 (7q11.22) exon 2-4 were the molecular lesions specific to tumors and were frequently detected in B-NHL samples. These IERs constitute novel genetic alterations of B-NHL, which might be associated with tumorigenesis and be useful as genetic biological markers. Show less

Eukaryotic DNA replication starts with the assembly of a pre-replication complex (pre-RC) at replication origins. We have previously demonstrated that Metaphase Chromosome Protein 1 (MCP1) is involved in the early events of DNA replication. Here we show that MCP1 associates with proteins that are required for the establishment of the pre-replication complex. Reciprocal immunoprecipitation analysis showed that MCP1 interacted with Cdc6, ORC2, ORC4, MCM2, MCM3 and MCM7, with Cdc45 and PCNA. Immunofluorescence studies demonstrated the co-localization of MCP1 with some of those proteins. Moreover, biochemical studies utilizing chromatin-immunoprecipitation (ChIP) revealed that MCP1 preferentially binds replication initiation sites in human cells. Interestingly, although members of the pre-RC are known to interact with some hallmarks of heterochromatin, our co-immunoprecipitation and immunofluorescence analyses showed that MCP1 did not interact and did not co-localize with heterochromatic proteins including HP1β and MetH3K9. These observations suggest that MCP1 is associated with replication factors required for the initiation of DNA replication and binds to the initiation sites in loci that replicate early in S-phase. In addition, immunological assays revealed the association of MCP1 forms with histone H1 variants and mass spectrometry analysis confirmed that MCP1 peptides share common sequences with H1.2 and H1.5 subtypes. Show less

Carbamoylphosphate synthetase I deficiency (CPS1D) is a urea-cycle disorder characterized by episodes of life-threatening hyperammonemia. Correct diagnosis is crucial for patient management, but is difficult to make from clinical presentation and conventional laboratory tests alone. Enzymatic or genetic diagnoses have also been hampered by difficult access to the appropriate organ and the large size of the gene (38 exons). In this study, in order to address this diagnostic dilemma, we performed the largest mutational and clinical analyses of this disorder to date in Japan. Mutations in CPS1 were identified in 16 of 18 patients with a clinical diagnosis of CPS1D. In total, 25 different mutations were identified, of which 19 were novel. Interestingly, in contrast to previous reports suggesting an extremely diverse mutational spectrum, 31.8% of the mutations identified in Japanese were common to more than one family. We also identified two common polymorphisms that might be useful for simple linkage analysis in prenatal diagnosis. The accumulated clinical data will also help to reveal the clinical presentation of this rare disorder in Japan. Show less