Identifying a Novel Pathway to Platinum Resistance in Ovarian Cancer
Posted: Thursday, December 5, 2019
The relationship between extracellular regulated kinase (ERK) and hypoxia-inducible factor (HIF-1α) may prove to play a central role in platinum resistance in ovarian cancer cells, according to Wenge Zhu, PhD, of the George Washington (GW) School of Medicine in Washington, DC, and colleagues. The researchers published their study in Clinical Cancer Research.
“We found that HIF-1α stabilization is regulated by the TGF-β1/ERK/PHD2 axis in platinum-resistant ovarian cancer cells. Now, we can consider inhibiting any of those components as a potential strategy for treating platinum-resistant patients,” Dr. Zhu concluded in a GW press release.
Through in vitro and in vivo experiments, researchers focused on a combination of inhibitors: the HIF-1α inhibitor YC-1; the ERK inhibitor selumetinib; and the TGF-β1 inhibitor SB431542. Researchers also used a quantitative high-throughput combinational screen to identify novel drugs that could resensitize platinum-resistant ovarian cells to cisplatin.
Elevated levels of HIF-1α in platinum-resistant ovarian cells were reduced with the combined treatment of YC-1 and cisplatin, and YC-1 also assisted in overcoming cisplatin resistance, according to the investigators. The prolyl hydroxylase domain-containing protein 2 (PHD2) was shown to be a direct substrate of ERK, and the phosphorylation of PHD2 increased HIF-1α stability by ERK, preventing the binding to HIF-1α and inhibiting its hydroxylation and degradation. Furthermore, inhibition of TGF-β1 by SB431542, ERK by selumetinib, or HIF-1α by YC-1 efficiently overcame platinum resistance both in vitro and in vivo.
Disclosure: The authors’ disclosure information can be found at clincancerres.aacrjournals.org.