Scientists at Sanford-Burnham have confirmed that PDK1 gene expression is essential for formation and metastasis of melanoma tumors. This is the first study showing the relationship between PDK1 and melanoma, the deadliest form of skin cancer. The study, performed in collaboration with researchers at the Department of Dermatology, Medicine, and Pathology, Yale University, is published in the advanced online publication of Oncogene.
Ze’ev Ronai, Ph.D., scientific director of Sanford-Burnham Medical Research Institute at La Jolla, and his team as well as collaborators at Yale University, used genetic mouse models lacking the PDK1 gene to show that without PDK1 expression, melanoma tumors were smaller in size, had a significant loss of metastasis, and a prolonged survival—in some cases survival time was increased to over 50 percent— in other cases melanoma was completely prevented.
The PDK1 gene was previously known to play an important role in normal cell processes, such as metabolism, protein translation, and cell survival under stress conditions. PDK1 was also implicated in some types of cancer, such as pancreatic cancer, but not others, such as non-small cell lung cancer. This is the first study that shows the negative role that PDK1 expression plays in melanocytes (cells that will transform to melanoma).
In addition to using mice that lacked the PDK1 gene, the team of researchers used a PDK1 inhibitor (PDK1i) in wild-type mice to show that they could delay melanomagenesis and metastasis. “With these findings, scientists are now clear that the cancer field should invest more in PDK1 targets.” said Meenhard Herlynn , D.V.M., D.Sc., Director of Melanoma Research and Leader of the Molecular and Cellulary Oncogenesis Program at the The Wistar Institute in Philadelphia, PA.
Today, there is no cure for metastatic melanoma. Treatment regimens for patients include surgery, chemotherapy, and administration of drugs that stimulate the immune system to fight the cancer. Kinase inhibitors, such BRAF inhibitors are also added to the mix of drugs to form a “cocktail” that aims to improve patient survival.
“It is important now to demonstrate the impact of PDK1 expression in combination with other therapies used for melanoma treatment. A number of PDKi are available and others under development. Ultimately, our goal is to see if inhibition of PKD1 will contribute to better outcomes for patients with melanoma,” Ronai said.
Scortegagna M, Ruller C, Feng Y, Lazova R, Kluger H, Li JL, De SK, Rickert R, Pellecchia M, Bosenberg M, & Ronai ZA (2013). Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of BrafV600E::Pten-/- melanoma. Oncogene PMID: 24037523