The American Cancer Society estimates that almost 14,000 women in the United States alone will die from ovarian cancer in 2019. Additionally, with cancer drug resistance rates on the rise, having a greater understanding of the underlying molecular mechanisms that lead to chemotherapy resistance is critical. Now, investigators at the George Washington University (GW) Cancer Center have identified that the extracellular regulated kinase (ERK) protein is an important mechanism behind platinum-resistance in platinum-resistant ovarian cancer.

Findings from the new study—published recently in Clinical Cancer Research through an article titled “ERK Regulates HIF1α-Mediated Platinum Resistance by Directly Targeting PHD2 in Ovarian Cancer”—provide clinical evidence confirming a link between ERK and hypoxia-inducible factor (HIF-1α).

Platinum-based chemotherapy drugs are among the strongest and most widely used against cancer. Up to 80% of ovarian cancer patients develop platinum-resistance over the course of their treatment. Studies have found that HIF-1α—a subunit of HIF-1, a heterodimeric transcription factor that regulates multiple cellular pathways—is an important mechanism governing platinum resistance. However, the mechanism regulating HIF-1α stability in platinum-resistant ovarian cancer was largely unknown.

“Platinum-based chemotherapy is such a powerful treatment for cancer patients, however so many develop a resistance,” explained senior study investigator Wenge Zhu, PhD, associate professor of biochemistry and molecular medicine at the GW School of Medicine and Health Sciences. “We wanted to figure out how that resistance happens for the cancer cells.”

The research team evaluated a combination of inhibitors of HIF-1α, ERK, and TGF-β1 with platinum drugs by in vitro and in vivo experiments. They found prolyl hydroxylase domain-containing protein 2 (PHD2) to be an underlying layer of ERK. Zhu and his team observed that from clinical samples the activation of the ERK/PHD2/HIF-1α axis in platinum-resistant ovarian cancer patients, correlated highly with poor prognoses for patients.

“We first used a quantitative high-throughput combinational screen (qHTCS) to identify novel drugs that could resensitize PROC cells to cisplatin. Next, we evaluated the combination efficacy of inhibitors of HIF1α (YC-1), ERK (selumetinib), and TGFβ1 (SB431542) with platinum drugs by in vitro and in vivo experiments. Moreover, a novel TGFβ1/ERK/PHD2-mediated pathway regulating HIF1α stability in platinum-resistant ovarian cancer (PROC) was discovered.”

“We found that HIF-1α stabilization is regulated by the TGF-β1/ERK/PHD2 axis in platinum-resistant ovarian cancer cells,” Zhu said. “Now we can consider inhibiting any of those components as a potential strategy for treating platinum-resistant patients.”

This study also provides insight for further investigation into whether this novel mechanism regulates the development of tumors and future chemotherapy response.

“HIF1α stabilization is regulated by TGFβ1/ERK/PHD2 axis in PROC. Hence, inhibiting TGFβ1, ERK, or HIF1α is a potential strategy for treating patients with PROC,” the authors concluded.

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