Melanoma: PDK1 Kinase Required for Development and Metastasis

Ze'ev Ronai, Ph.D., Professor and scientific director of Sanford-Burnham Medical Research Institute La Jolla San Diego, Interview with:
Ze’ev Ronai, Ph.D.
Professor and scientific director of Sanford-Burnham Medical Research Institute La Jolla San Diego, Calif. What are the main findings of the study?

Answer: This study provides the first direct evidence of the importance of the PDK1 enzyme in the development of melanoma and in the metastasis of this aggressive tumor type. We demonstrate, with a genetic mouse melanoma model (harboring the Braf/Pten mutations commonly seen in human melanomas) and/or pharmacological inhibitors against PDK1, that melanoma requires this enzyme for its development, and more so – for its ability to metastasize. Since PDK1 is key kinase that regulates a number of protein kinases, which are currently being assessed in clinical trials (including AKT), our finding points to a new set of targets that could be more amenable for effective combination therapy in melanoma. Were any of the findings unexpected?

Answer: We were surprised by the degree of inhibition seen in melanoma metastasis using the genetic model, and even more so by how much of the PDK1 activity was AKT-independent, thereby pointing to kinases other than AKT that are regulated by PDK1 as mediators of melanoma development. What should clinicians and patients take awayfrom your report?

Answer: These findings point to a possible new tangible therapeutic target for melanoma therapy. Since PDK1 inhibitors arecurrently in clinical trials, and others are at advance stages of development, they should be considered for combination therapy with Braf inhibitors, MEK inhibitors or immunotherapies (PD1 inhibitors).  What recommendations do you have for future research as a result of this study?

Answer: We are excited about these findings and plan to extend them to better understand which of the >20 kinases regulated by PDK1 is required for the development and metastasis of melanoma, and which of the melanoma patient tumors are more amenable for treatment with PDK1 inhibitors. Validation of our findings in other laboratories, including some of the pharmaceutical companies that have PDK1 inhibitors would be a logical step forward in further assessing PDK1 as melanoma target for therapy.


Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of BrafV600E::Pten–/– melanoma

M Scortegagna, C Ruller, Y Feng, R Lazova, H Kluger, J-L Li, S K De, R Rickert, M Pellecchia, M Bosenberg and Z A Ronai
Oncogene , (16 September 2013) | doi:10.1038/onc.2013.383