Co-targeting of FGFR Signaling in Metastatic Uveal Melanoma
Posted: Wednesday, January 16, 2019
Andrew E. Aplin, PhD, of Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, and colleagues attempted to learn why liver metastases progressed rapidly after treatment of patients for uveal melanoma; in fact, studies have shown that about 50% of patients with uveal melanoma develop metastases. Through their research into the mechanisms of resistance to bromodomain and extraterminal (BET) protein inhibitors, they discovered that co-targeting of fibroblast growth factor 2 (FGFR) signaling may be needed to improve responses to these agents in this patient population. Their research findings were published in EMBO Molecular Medicine.
“Inhibition of BET proteins is emerging as a promising anticancer therapeutic strategy to block transcriptional dependencies,” revealed the investigators. “In vivo analysis of BET and FGFR inhibitor effects on [uveal melanoma] xenografts show poor responses of tumors to BET inhibition, and this was reversed by an FGFR inhibitor.”
Dr. Aplin’s team used cell-based assays and patient samples to study the regulation by growth factors in the tumor microenvironment on the efficacy of BET inhibitors, including PLX51107. They found that responses to BET inhibition were reduced by paracrine secretion of FGF2 by stromal cells in the tumor microenvironment. In addition, they found evidence of increased expression of receptors in the FGFR pathway in response to this type of treatment. The effects of FGF2 were found to be reversible by FGFR inhibitors, such as AZD4547.
“PLX51107 was ineffective in vivo, but the combination of an FGFR inhibitor, AZD4547, and PLX51107 significantly suppressed the growth of xenograft [uveal melanoma] tumors formed from subcutaneous inoculation of [uveal melanoma] cells with [hepatic stellate cells] and orthotopically in the liver,” the investigators concluded.
Disclosure: The study authors’ disclosure information may be found at embopress.org.