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Ref Type Journal Article
PMID (37270847)
Authors Subbiah V, Sahai V, Maglic D, Bruderek K, Toure BB, Zhao S, Valverde R, O'Hearn PJ, Moustakas DT, Schonherr H, Gerami-Moayed N, Taylor AM, Hudson BM, Houde DJ, Pal D, Foster L, Gunaydin H, Ayaz P, Sharon DA, Goyal L, Schram AM, Kamath S, Sherwin CA, Schmidt-Kittler O, Jen KY, Ricard F, Wolf BB, Shaw DE, Bergstrom DA, Watters J, Casaletto JB
Title RLY-4008, the first highly selective FGFR2 inhibitor with activity across FGFR2 alterations and resistance mutations.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 2023 Jun 04 Cancer Discov
URL
Abstract Text Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting of FGFR2 has not been achieved. While the clinical efficacy of pan-FGFR inhibitors (pan-FGFRi) validates FGFR2 driver status in FGFR2 fusion-positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- and FGFR4-mediated toxicities (hyperphosphatemia and diarrhea) and the emergence of FGFR2 resistance mutations. RLY 4008 is a highly selective, irreversible FGFR2 inhibitor designed to overcome these limitations. In vitro, RLY-4008 demonstrates >250- and >5000-fold selectivity over FGFR1 and FGFR4, respectively, and targets primary alterations and resistance mutations. In vivo, RLY-4008 induces regression in multiple xenograft models - including models with FGFR2 resistance mutations that drive clinical progression on current pan-FGFRi - while sparing FGFR1 and FGFR4. In early clinical testing, RLY-4008 induced responses without clinically significant off-isoform FGFR toxicities, confirming the broad therapeutic potential of selective FGFR2 targeting.

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