Researchers at Mayo Clinic in Jacksonville, Fla., are reporting they have discovered genetic evidence that guanine nucleotide exchange factor (GEF) epithelial cell transforming sequence 2 (Ect2) drives lung adenocarcinoma tumor formation. The researchers note that Ect2 in the past has been associated with cancer. However, this paper demonstrates for the first time that Ect2 is required for tumor formation in vivo and identifies a novel function related to ribosomes.

“Ect2 drives increased synthesis of ribosomal RNA, which in turn gives rise to increased ribosomes,” said senior author Alan Fields, PhD, a cancer biologist and a Professor of Cancer Research in the Department of Cancer Biology at Mayo Clinic’s Florida campus. “While it’s been known for a long time that tumor cells have elevated ribosome levels, this paper is the first to show that Ect2 supports tumor cell growth by stimulating ribosome biogenesis.”

Fields said lung adenocarcinoma accounts for 40% of lung cancer diagnoses and the most frequent driver of this cancer is a mutation in the KRAS gene. To date, agents that directly target KRAS have seen disappointing results and there is an acute unmet clinical need, according to the study’s lead author Verline Justilien, PhD, an assistant professor in the Department of Cancer Biology at Mayo Clinic’s Florida campus. Ect2 role differs when it comes to cancer cells. In normal cells, Ect2 directs cytokinesis. However, Fields and colleagues have discovered that Ect2 is not necessary for cytokinesis in lung adenocarcinoma cells.

In their previous studies, the researchers implicated another lung cancer gene, protein kinase CI (PKCI) in controlling the activity of Ect2 in this disease model. They demonstrated that auranofin, which is a PKCI inhibitor, shuts down lung adenocarcinoma tumor growth when combined with a second experimental agent. The current Cancer Cell paper indicates that inhibition of Ect2, and subsequently ribosome synthesis, is a major mechanism by which auranofin works. The research team reports that Ect2 regulates rRNA synthesis through a PKCI-Ect2-Rac1-NPM signaling axis that is required for lung tumorigenesis.

Based on preclinical research from Dr. Fields’ team, Mayo Clinic is conducting early-phase clinical trials with auranofin. The studies will test the effectiveness of the compound alone and in targeted combinations. The trials will focus on patients with KRAS-mediated lung adenocarcinoma as well as patients with lung squamous cell carcinoma and ovarian cancer.

The researchers write that these new discoveries provide a new mechanistic insight into Ect2-mediated transformation and establish a functional link between Ect2-dependent ribosome biogenesis and tumorigenesis in lung adenocarcinoma. The data also support a new therapeutic strategy for treating KRAS-driven lung adenocarcinoma.

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