Poulikos Poulikakos, PhD Email Poulikos Poulikakos
- ASSOCIATE PROFESSOR | Oncological Sciences
Biochemistry, Breast Cancer, Cancer, Cell Biology, Cell Cycle, Dermatology, Drug Design and Discovery, Drug Resistance, Phosphorylation, Protein Kinases, Signal Transduction, Translational Research, Tumor Suppressor Genes
PhD, University of Athens, School of Biology
, Fox Chase Cancer Center
, Memorial Sloan-Kettering Cancer Center
Research Career Developmenet Award
Unraveling mechanistic requirements for RAF dimerization, catalytic activation and response to kinase inhibitors
Tisch Cancer Institute Developmental Award
Identification of effective therapeutic strategies against RAF-inhibitor resistant melanoma
The Harry J. Lloyd Charitable Trust
Molecular Determinants of Tumor Dependence on ERK Signaling
CY14 Developmental Research Pilot Project Program
RSK Kinase as a mediator of oncogenic ERK signaling and a novel therapeutic Target in Melanoma
TCI Young Scientist Cancer Research Award
Using small molecule compounds to dissect and target oncogenic signaling.
We use small molecule inhibitors to acutely disrupt oncogenic signal transduction networks. Our goal is to understand the regulation of their components and their role in tumor maintenance and resistance to targeted therapies. Current research in the lab focuses on elucidating the complex biologic and biochemical effects of components of the RAS/RAF/MEK/ERK pathway (ERK signaling) in cancer in order to design mechanism-based therapeutic strategies.
Biochemical and biological properties of RAF inhibitors
The discovery that established tumors usually remain dependent on signaling pathways activated by mutationally activated oncoproteins led to the idea that targeted inhibition of components of these pathways would be especially effective for therapy. The RAS/RAF/MEK/ERK signaling pathway (ERK signaling) regulates key cellular processes, such as cell proliferation, differentiation and survival and has been found deregulated in about a third of human cancers. Hyperactivation of ERK signaling is especially prevalent in malignant melanomas. About 50% of these tumors contain BRAF mutations (almost exclusively V600E), whereas 15%–30% contain mutations in NRAS.
Melanoma tumors expressing the mutant BRAF(V600E) almost universally depend on it for growth. This led to the aggressive development of inhibitors of ERK signaling as potential therapeutics. In general, kinase inhibitors (e.g. MEK inhibitors) inhibit their target in all cells. In contrast, RAF inhibitors affect ERK signaling in a mutation-specific manner: they inhibit ERK signaling in cells with BRAF(V600E), but paradoxically activate ERK signaling in cells with wild-type BRAF. The underlying mechanism of this phenomenon is summarized in the following model (Poulikakos PI et al., Nature, 2010): Activation of RAS promotes the dimerization of members of the RAF family. Binding of an ATP-competitive RAFinhibitor to one member of the dimer inhibits it while also causing its transition to the active state. This is associated with the allosteric transactivation of the other, unbound member of the dimer, resulting in a marked increase in RAF specific activity and induction of ERK signaling. RAF induction by inhibitor requires levels of RAS activity sufficient to support formation of RAF dimers. In BRAF(V600E) melanomas, RAS-GTP levels are inadequate and RAF inhibitors inhibit the active RAF monomers. This model predicts that RAF inhibitors will have a wide therapeutic index in patients with mutant BRAF tumors, but that they could cause toxicity by activating ERK signaling in normal cells. Clinical trials of RAF inhibitors in metastatic melanoma emphatically confirmed these predictions.
BRAF splicing variants as a novel mechanism of resistance to RAF inhibitors in melanoma
The model of RAF transactivation by RAF inhibitors predicts that any molecular lesion that enhances RAF dimerization will promote resistance to RAF inhibitors. These could include changes that cause increased activation of RAS and alterations in RAF that cause it to dimerize in a RAS-independent manner. We identified a novel mechanism of acquired resistance to RAF inhibitors in preclinical models and patients: expression of aberrant splicing variants of BRAF(V600E) that lack the RAS-binding domain and therefore dimerize in a RAS-independent manner (Poulikakos PI et al., Nature, 2011).
Major areas of research in the lab include:
1. Understand RAF kinase regulation and function in signaling and disease.
2. Elucidate mechanisms of resistance to RAF and MEK inhibitors and develop rationally-designed therapeutic strategies to overcome resistance in melanoma.
3. Investigate novel approaches to target RAS and RAF mutant tumors.
Postdoctoral Fellows: Zoi Karoulia, Tamer Ahmed
Visit the Poulikakos Lab
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Dr.Poulikakos did not report having any of the following types of financial relationships with industry during 2019 and/or 2020: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
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