PhD, University of Athens, School of Biology
, Fox Chase Cancer Center
, Memorial Sloan-Kettering Cancer Center
Identification of effective therapeutic strategies against RAF-inhibitor resistant melanoma
The Harry J. Lloyd Charitable Trust
Research Career Developmenet Award
RSK Kinase as a mediator of oncogenic ERK signaling and a novel therapeutic Target in Melanoma
TCI Young Scientist Cancer Research Award
Unraveling mechanistic requirements for RAF dimerization, catalytic activation and response to kinase inhibitors
Tisch Cancer Institute Developmental Award
Molecular Determinants of Tumor Dependence on ERK Signaling
CY14 Developmental Research Pilot Project Program
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
Lito P, Pratilas CA, Joseph EW, Tadi M, Halilovic E, Zubrowski M, Huang A, Wong WL, Callahan MK, Merghoub T, Wolchok JD, de Stanchina E, Chandarlapaty S, Poulikakos PI, Fagin JA, Rosen N. Relief of Profound Feedback Inhibition of Mitogenic Signaling by RAF Inhibitors Attenuates Their Activity in BRAFV600E Melanomas. Cancer cell 2012 Nov; 22(5).
Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, Gabay MT, Salton M, Dahlman KB, Tadi M, Wargo JA, Flaherty KT, Kelley MC, Misteli T, Chapman PB, Sosman JA, Graeber TG, Ribas A, Lo RS, Rosen N, Solit DB. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 2011 Dec; 480(7377).
Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel E, Baselga J, Guichard S, Rosen N. mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer discovery 2011 Aug; 1(3).
Poulikakos PI, Solit DB. Resistance to MEK inhibitors: should we co-target upstream?. Science signaling 2011; 4(166).
Poulikakos PI, Rosen N. Mutant BRAF melanomas--dependence and resistance. Cancer cell 2011 Jan; 19(1).
Joseph EW, Pratilas CA, Poulikakos PI, Tadi M, Wang W, Taylor BS, Halilovic E, Persaud Y, Xing F, Viale A, Tsai J, Chapman PB, Bollag G, Solit DB, Rosen N. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proceedings of the National Academy of Sciences of the United States of America 2010 Aug; 107(33).
Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010 Mar; 464(7287).
Li J, Poulikakos PI, Dai Z, Testa JR, Callaway DJ, Bu Z. Protein kinase C phosphorylation disrupts Na+/H+ exchanger regulatory factor 1 autoinhibition and promotes cystic fibrosis transmembrane conductance regulator macromolecular assembly. The Journal of biological chemistry 2007 Sep; 282(37).
Mabuchi S, Altomare DA, Cheung M, Zhang L, Poulikakos PI, Hensley HH, Schilder RJ, Ozols RF, Testa JR. RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clinical cancer research : an official journal of the American Association for Cancer Research 2007 Jul; 13(14).
Poulikakos PI, Xiao GH, Gallagher R, Jablonski S, Jhanwar SC, Testa JR. Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK. Oncogene 2006 Sep; 25(44).
Wang HQ, Altomare DA, Skele KL, Poulikakos PI, Kuhajda FP, Di Cristofano A, Testa JR. Positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells. Oncogene 2005 May; 24(22).
Apostolou S, Klein JO, Mitsuuchi Y, Shetler JN, Poulikakos PI, Jhanwar SC, Kruger WD, Testa JR. Growth inhibition and induction of apoptosis in mesothelioma cells by selenium and dependence on selenoprotein SEP15 genotype. Oncogene 2004 Jun; 23(29).
Nechamen CA, Thomas RM, Cohen BD, Acevedo G, Poulikakos PI, Testa JR, Dias JA. Human follicle-stimulating hormone (FSH) receptor interacts with the adaptor protein APPL1 in HEK 293 cells: potential involvement of the PI3K pathway in FSH signaling. Biology of reproduction 2004 Aug; 71(2).
Poulikakos P, Vassilacopoulou D, Fragoulis EG. L-DOPA decarboxylase association with membranes in mouse brain. Neurochemical research 2001 May; 26(5).
Chakravarty SD, Poulikakos PI, Ivashkiv LB, Salmon JE, Kalliolias GD. Kinase inhibitors: a new tool for the treatment of rheumatoid arthritis. Clinical immunology (Orlando, Fla.) 2013 Jul; 148(1).
Ishii N, Harada N, Joseph EW, Ohara K, Miura T, Sakamoto H, Matsuda Y, Tomii Y, Tachibana-Kondo Y, Iikura H, Aoki T, Shimma N, Arisawa M, Sowa Y, Poulikakos PI, Rosen N, Aoki Y, Sakai T. Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity. Cancer research 2013 Jul; 73(13).
Chakraborty R, Hampton OA, Shen X, Simko SJ, Shih A, Abhyankar H, Lim KP, Covington KR, Trevino L, Dewal N, Muzny DM, Doddapaneni H, Hu J, Wang L, Lupo PJ, Hicks MJ, Bonilla DL, Dwyer KC, Berres ML, Poulikakos PI, Merad M, McClain KL, Wheeler DA, Allen CE, Parsons DW. Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood 2014 Nov; 124(19).
Samatar AA, Poulikakos PI. Targeting RAS-ERK signalling in cancer: promises and challenges. Nature reviews. Drug discovery 2014 Dec; 13(12).
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Dr.Poulikakos did not report having any of the following types of financial relationships with industry during 2015 and/or 2016: 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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