BACKGROUND: The fibroblast growth factor receptor (FGFR) signaling pathway is activated in multiple tumor types through gene amplifications, single base substitutions, or gene fusions. Multiple small molecule kinase inhibitors targeting FGFR are currently being evaluated in clinical trials for patients with FGFR chromosomal translocations. Patients with novel gene fusions involving FGFR may represent candidates for kinase inhibitors. METHODS: A targeted RNA-sequencing assay identified a KLK2-FGFR2 fusion gene in two patients with metastatic prostate cancer. NIH3T3 cells were transduced to express the KLK2-FGFR2 fusion. Migration assays, Western blots, and drug sensitivity assays were performed to functionally characterize the fusion. RESULTS: Expression of the KLK2-FGFR2 fusion protein in NIH3T3 cells induced a profound morphological change promoting enhanced migration and activation of downstream proteins in FGFR signaling pathways. The KLK2-FGFR2 fusion protein was determined to be highly sensitive to the selective FGFR inhibitors AZD-4547, BGJ398, JNJ-42756943, the irreversible inhibitor TAS-120, and the non-selective inhibitor Ponatinib. The KLK2-FGFR2 fusion did not exhibit sensitivity to the non-selective inhibitor Dovitinib. CONCLUSIONS: Importantly, the KLK2-FGFR2 fusion represents a novel target for precision therapies and should be screened for in men with prostate cancer.
BACKGROUND: The fibroblast growth factor receptor (FGFR) signaling pathway is activated in multiple tumor types through gene amplifications, single base substitutions, or gene fusions. Multiple small molecule kinase inhibitors targeting FGFR are currently being evaluated in clinical trials for patients with FGFR chromosomal translocations. Patients with novel gene fusions involving FGFR may represent candidates for kinase inhibitors. METHODS: A targeted RNA-sequencing assay identified a KLK2-FGFR2 fusion gene in two patients with metastatic prostate cancer. NIH3T3 cells were transduced to express the KLK2-FGFR2 fusion. Migration assays, Western blots, and drug sensitivity assays were performed to functionally characterize the fusion. RESULTS: Expression of the KLK2-FGFR2 fusion protein in NIH3T3 cells induced a profound morphological change promoting enhanced migration and activation of downstream proteins in FGFR signaling pathways. The KLK2-FGFR2 fusion protein was determined to be highly sensitive to the selective FGFR inhibitors AZD-4547, BGJ398, JNJ-42756943, the irreversible inhibitor TAS-120, and the non-selective inhibitor Ponatinib. The KLK2-FGFR2 fusion did not exhibit sensitivity to the non-selective inhibitor Dovitinib. CONCLUSIONS: Importantly, the KLK2-FGFR2 fusion represents a novel target for precision therapies and should be screened for in men with prostate cancer.
Authors: Melanie A Krook; Alexandria Lenyo; Max Wilberding; Hannah Barker; Mikayla Dantuono; Kelly M Bailey; Hui-Zi Chen; Julie W Reeser; Michele R Wing; Jharna Miya; Eric Samorodnitsky; Amy M Smith; Thuy Dao; Dorrelyn M Martin; Kristen K Ciombor; John Hays; Aharon G Freud; Sameek Roychowdhury Journal: Mol Cancer Ther Date: 2020-01-07 Impact factor: 6.261
Authors: Jun Li; Hengyu Lu; Patrick Kwok-Shing Ng; Angeliki Pantazi; Carman Ka Man Ip; Kang Jin Jeong; Bianca Amador; Richard Tran; Yiu Huen Tsang; Lixing Yang; Xingzhi Song; Turgut Dogruluk; Xiaojia Ren; Angela Hadjipanayis; Christopher A Bristow; Semin Lee; Melanie Kucherlapati; Michael Parfenov; Jiabin Tang; Sahil Seth; Harshad S Mahadeshwar; Kamalika Mojumdar; Dong Zeng; Jianhua Zhang; Alexei Protopopov; Jonathan G Seidman; Chad J Creighton; Yiling Lu; Nidhi Sahni; Kenna R Shaw; Funda Meric-Bernstam; Andrew Futreal; Lynda Chin; Kenneth L Scott; Raju Kucherlapati; Gordon B Mills; Han Liang Journal: Sci Adv Date: 2022-02-09 Impact factor: 14.136