The oncogenic effects of PI3K activation: the good, the bad, and the surprising
Aberrant activation of the PI3K pathway is one the most common oncogenic events in human tumours. The clinical success and regulatory approval of idelalisib, a PI3Kδ inhibitor, for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin’s lymphoma, validate the importance of the pathway in human malignancies. However, compared to the high frequency of PI3K activation in human cancer, response rates to other PI3K-targeted therapies remain low, highlighting the need for a better understanding of how PI3K-dependent signals regulate cell survival in specific genetic contexts.
Whether PI3K itself is an oncogenic driver in human tumours, or whether it acts as an “active passenger” (i.e. one that influences the functional output of the driver), will determine its potential as a therapeutic target.
The serine/threonine kinase Akt is a critical PI3K effector that promotes a number of cancer-associated phenotypes, including cell survival. Consequently, a number of pharmacological agents directly targeting Akt have been developed and are currently undergoing clinical evaluation. However, the clinical experience so far has been disappointing, suggesting that either AKT is not the only (or the primary) PI3K-dependent effector responsible for cell survival in PI3K-active tumours, or that pharmacological approaches have been inadequate.
Our work has focused on understanding the contribution of PI3K to cancer cell survival in a variety of cell-type- and genetic-specific contexts. We have also been interested in using comparative pharmacology to probe different aspects of PI3K and AKT function to understand how these signals are transduced into cell survival effects. I will discuss a number of projects that have helped us understand PI3K/AKT-dependent regulation of cancer cell survival.
About the Speaker:
A native of Peru, Dr Vivanco received his BA in Molecular and Cellular Biology from the University of California at Berkeley, and his PhD in Molecular Biology from the University of California at Los Angeles. As a graduate student in the laboratory of Dr Charles Sawyers, Dr Vivanco became interested in the study of oncogene addiction, around the time when clinical validation of this concept was being brought forth with the results of the first Imatinib clinical trials.
During his graduate studies with Dr Sawyers, Dr Vivanco focused on understanding the biochemical consequences resulting from the loss of the tumour suppressor PTEN. He found that functional inactivation of PTEN increased the activity of Jun-N-terminal kinases (JNKs) and enhanced the dependence of cells on the activity of JNK. He showed that compounds that target JNK kinase can inhibit the growth of PTEN-deficient cells while having minimal effects on PTEN-intact cells.
After receiving his PhD, Dr Vivanco continued to study oncogene addiction in the laboratory of Dr Ingo Mellinghoff at Memorial Sloan Kettering Cancer Center, where he focused on the study of oncogenic EGFR. He co-authored a study that provided clinical evidence of PTEN loss as a mechanism of de novo EGFR inhibitor resistance in glioblastoma (GBM), and subsequently showed that this resistance is primarily caused by a PTEN-sensitive defect in active EGFR turnover. Furthermore, using in vitro and in vivo models and comparative pharmacology, Dr. Vivanco has demonstrated that the specific location of activating mutations in EGFR will cause differential shifts in the conformational equilibrium of the kinase such that certain mutations favour binding of Type I inhibitors (e.g. EGFR mutants found in lung cancer) while others favour Type 2 inhibitor binding (e.g. EGFR mutants found in glioblastoma). His studies have provided proof-of-concept for ongoing clinical trials of EGFR inhibitors in glioblastoma.
In the last few years, Dr Vivanco has been working on trying to understand the molecular basis of addiction to PI3K. He hopes that through molecular characterization of the specific contributions of pathway components to cancer cell survival, he will be able to devise novel therapeutic strategies across a variety of cancer types. His group uses biochemical tools and comparative pharmacology to interrogate the consequences of pathway perturbations on cancer cell viability. He has recently identified a novel function of Akt that does not depend on catalytic activity. His laboratory is currently working on characterizing the molecular identity of this novel pathway.