TY - JOUR
T1 - RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations
AU - Subbiah, Vivek
AU - Sahai, Vaibhav
AU - Maglic, Dejan
AU - Bruderek, Kamil
AU - Touré, B. Barry
AU - Zhao, Songping
AU - Valverde, Roberto
AU - O’hearn, Patrick J.
AU - Moustakas, Demetri T.
AU - Schönherr, Heike
AU - Gerami-Moayed, Nastaran
AU - Taylor, Alexander M.
AU - Hudson, Brandi M.
AU - Houde, Damian J.
AU - Pal, Debjani
AU - Foster, Lindsey
AU - Gunaydin, Hakan
AU - Ayaz, Pelin
AU - Sharon, Dina A.
AU - Goyal, Lipika
AU - Schram, Alison M.
AU - Kamath, Suneel
AU - Sherwin, Cori Ann
AU - Schmidt-Kittler, Oleg
AU - Jen, Kai Yu
AU - Ricard, Fabien
AU - Wolf, Beni B.
AU - Shaw, David E.
AU - Bergstrom, Donald A.
AU - Watters, James
AU - Casaletto, Jessica B.
N1 - Publisher Copyright:
© 2023 The Authors, Published by the American Association for Cancer Research.
PY - 2023/9
Y1 - 2023/9
N2 - 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. Although 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 (hyperphos-phatemia and diarrhea, respectively) 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 >5,000-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. SIGNIFICANCE: Patients with FGFR2-driven cancers derive limited benefit from pan-FGFRi due to multiple FGFR1–4-mediated toxicities and acquired FGFR2 resistance mutations. RLY-4008 is a highly selective FGFR2 inhibitor that targets primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs, suggesting it may have broad therapeutic potential.
AB - 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. Although 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 (hyperphos-phatemia and diarrhea, respectively) 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 >5,000-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. SIGNIFICANCE: Patients with FGFR2-driven cancers derive limited benefit from pan-FGFRi due to multiple FGFR1–4-mediated toxicities and acquired FGFR2 resistance mutations. RLY-4008 is a highly selective FGFR2 inhibitor that targets primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs, suggesting it may have broad therapeutic potential.
UR - http://www.scopus.com/inward/record.url?scp=85165856983&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85165856983&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-23-0475
DO - 10.1158/2159-8290.CD-23-0475
M3 - Article
C2 - 37270847
AN - SCOPUS:85165856983
SN - 2159-8274
VL - 13
SP - 2012
EP - 2031
JO - Cancer discovery
JF - Cancer discovery
IS - 9
ER -