RLY-4008, the first highly selective FGFR2 inhibitor with activity across FGFR2 alterations and resistance mutations Journal Article
| Authors: | Subbiah, V.; Sahai, V.; Maglic, D.; Bruderek, K.; Touré, B. B.; Zhao, S. P.; Valverde, R.; O'Hearn, P. J.; Moustakas, D. T.; Schönherr, H.; Gerami-Moayed, N.; Taylor, A. M.; Hudson, B. M.; Houde, D. J.; Pal, D.; Foster, L.; Gunaydin, H.; Ayaz, P.; Sharon, D. A.; Goyal, L.; Schram, A. M.; Kamath, S.; Sherwin, C. A.; Schmidt-Kittler, O.; Jen, K. Y.; Ricard, F.; Wolf, B. B.; Shaw, D. E.; Bergstrom, D. A.; Watters, J.; Casaletto, J. B. |
| Article Title: | RLY-4008, the first highly selective FGFR2 inhibitor with activity across FGFR2 alterations and resistance mutations |
| Abstract: | 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 (hyperphosphatemia 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. |
| Keywords: | identification; multicenter; open-label; fusions; bgj398; futibatinib; metastatic cholangiocarcinoma |
| Journal Title: | Cancer Discovery |
| Volume: | 13 |
| Issue: | 9 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2023-09-01 |
| Start Page: | 2012 |
| End Page: | 2031 |
| Language: | English |
| ACCESSION: | WOS:001168289200013 |
| DOI: | 10.1158/2159-8290.Cd-23-0475 |
| PROVIDER: | wos |
| PMCID: | PMC10481131 |
| PUBMED: | 37270847 |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF-- Source: Wos |
