FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids towards cholangiocarcinoma

Oncogenic FGFR Fusions Produce Centrosome and Cilia Defects by Ectopic Signaling

“…About 45% of the intrahepatic cholangiocarcinoma cases are coupled with FGFR2 fusion, half of which are with bicaudal C1 (BICC1) [149,175,177,[212][213][214][215]; identification of FGFR2-BICC1 in other types of cancer is rare [175] (Table 1). FGFR2-BICC1 transformed NIH3T3 cells that formed tumors in mice [175], and the xenografted FGFR2-BICC1 expressing liver organoids gave rise to tumors [267].…”

“…As a consequence of the chromosomal rearrangement, the FGFR2 3 UTR is truncated which results in upregulation of the FGFR2-BICC1 fusion protein [214]. FGFR2-BICC1 dimerizes likely via the sterile alpha motifs of BICC1 [268], leading to ligandindependent dimerization [149] and activation of the ERK MAP kinase, but not STAT3 or AKT signaling [175,212,267]. FGFR inhibitors were partially successful in targeting the oncogene-driven growth of cell lines, xenografts and patients' tumors [175,215,269,270]; acquired resistance through gatekeeper FGFR2-V564F mutation was also reported [270].…”

“…FGFR inhibitors were partially successful in targeting the oncogene-driven growth of cell lines, xenografts and patients' tumors [175,215,269,270]; acquired resistance through gatekeeper FGFR2-V564F mutation was also reported [270]. The FGFR2 V546F -BICC1 cells showed oncogene addiction that was fully inhibited by a synergistic effect of the FGFR and ERK MAP kinase pathway inhibitors [267].…”

“…Fusions of FGFR2 with the citron Rho-interacting kinase (CIT) were identified in non-small cell lung cancer and cholangiocarcinoma [215,217,218] (Table 1). FGFR2-CIT dimerized in cells, likely using the coiled-coil domain of CIT [149] (Figure 1), and induced oncogene addiction in Ba/F3 cells that was efficiently targeted by FGFR kinase inhibitors [267,299].…”

Build to understand biliary oncogenesis via organoids and FGFR2 fusion proteins

“…Whether this will be the panacea for FGFR-fusion positive ICC remains to be seenas in other cancers, such as lung adenocarcinoma and melanoma, the targeting of the FGF/MAPK pathway has been fraught with difficulty, not least the rapid evolution of tumor cells that are no longer sensitive to targeted FGFR or BRAF inhibitors. 16 Perhaps this is where the organoids developed by Cristinziano et al 3 have a lasting place in preclinical research. They could be used to model the most likely genetic outcomes of sustained FGFR2 inhibition and to screen for compounds that either re-sensitize resistant cancer cells to pemigatinib or can be used as second-or third-line therapies once targeted FGFR2-inhibitors are no longer effective.…”