Leveraging patient derived models of FGFR2 fusion positive intrahepatic cholangiocarcinoma to identify synergistic therapies

Abstract

Intrahepatic cholangiocarcinoma (ICC) remains a deadly malignancy lacking systemic therapies for advanced disease. Recent advancements include selective FGFR1–3 inhibitors for the 15% of ICC patients harboring fusions, although survival is limited by poor response and resistance. Herein we report generation of a patient-derived FGFR2 fusion-positive ICC model system consisting of a cell line, organoid, and xenograft, which have undergone complete histologic, genomic, and phenotypic characterization, including testing standard-of-care systemic therapies. Using these FGFR2 fusion-positive ICC models, we conducted an unbiased high-throughput small molecule screen to prioritize combination strategies with FGFR inhibition, from which HDAC inhibition together with pemigatinib was validated in vitro and in vivo as a synergistic therapy for ICC. Additionally, we demonstrate broad utility of the FGFR/HDAC combination for other FGFR fusion-positive solid tumors. These data are directly translatable and justify early phase trials to establish dosing, safety, and therapeutic efficacy of this synergistic combination.

Tackling FGFR3-driven bladder cancer with a promising synergistic FGFR/HDAC targeted therapy

“…We first revealed that quisinostat can downregulate FGFR3 expression. Interestingly, this is somewhat in contrast to our previous findings in cholangiocarcinoma with FGFR2 fusions, in which we found that quisinostat can upregulate the activation of FGFR and Erk signaling 28 . The exact mechanisms underlying these differences are currently under investigation.…”

“…The effects of erdafitinib and/or quisinostat on cell signaling and protein expression were examined by western blot as described previously with minor modifications 28 . Briefly, to determine the effects of erdafitinib and/or quisinostat on FGFR signaling, cells were first treated by quisinostat for 2 days, followed by the erdafitinib treatment for 3 h or 1 day and no serum starvation for 3 h. DMSO was used as treatment control.…”

“…Our previous studies developed novel models of cholangiocarcinoma with FGFR2 fusions to discover more efficient therapeutics 28 . This included unbiased high-throughput screening that identified pemigatinib, another selective FGFR inhibitor, and quisinostat, a second-generation pan-HDACi, as a synergistic combination.…”

Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance

“…The original genetic and epigenetic features and surrounding stroma as observed in the initial mass are usually maintained in subcutaneous or orthotopic tumours, which are thus the ideal model to predict therapeutic responses and are excellent tools in personalized medicine. Indeed, several studies have already used PDXs to examine CCA that harbour specific mutational patterns and to test the use of specific targeted therapies [85][86][87][88][89][90][91] . Nevertheless, the success of PDX engraftment is relatively low, depending on the primary tumour itself and the experimental design for tumour engraftment.…”

Intrahepatic Cholangiocarcinoma—Where Are We Now and Where Are We Going to?

“…According to the studies carried out so far, it is believed that lesions positive for EGFR, ERBB2 or KRAS mutations in their cells are associated with a more aggressive course of the disease, which obviously worsens the prognosis of patients [6]. One of the most recent discoveries, which may be of great importance in iCCA-targeted therapies, is genetic FGFR2-G3BP2 fusion [11][12][13]. This is why, now, due to the identification of numerous genetic abnormalities in iCCA cells, there are many potential opportunities for the use of new drug molecules that remain in clinical trials (pemigatinib, futibatinib or ivosidenib) [1,7,12].…”