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2 Editors D. Höller K. Koch Technical editor D. Höller Printed by KDD DRUCKTERMINAL, Nürnberg, Germany Cover Bianca Malmendier, Munich Photo shows the village of Cavtat (courtesy of André Nantel) ISBN This book contains abstracts submitted by participants of the EMBO conference Cellular signalling and cancer therapy held in May 2014 in Cavtat, Croatia. The editors cannot be held responsible for correctness of scientific information in individual abstracts. Material contained herein should be cited only with permission of author(s). 1

3 Organising committee Ivan Đikić Institute of Biochemistry II, University Hospital Frankfurt, Goethe University, Germany René Medema Netherlands Cancer Institute, The Netherlands Margaret Frame Edinburgh Cancer Research Centre, UK Conference managers Dr. Kerstin Koch Institute of Biochemistry II University Hospital Frankfurt Goethe University Frankfurt a. M./Germany Dr. Daniela Höller KNOWLEDGE:communicated vgmbh St. Valentinstr Meran/Italy 2

4 CONTENTS Preface I Welcome note... 4 II Practical issues... 5 III Sponsors... 7 IV Scientific Programme... 8 V Abstracts ) Oral presentations ) Posters VI Venue map VII List of participants

5 I - WELCOME NOTE Dear colleagues, We welcome you to the 1 st EMBO meeting on Cellular signalling and cancer therapy in Cavtat. This conference marks the start of a new series of meetings focusing on cancer signalling and, most importantly, translational aspects. It continues the tradition of cell signalling meetings established in Cavtat in The detailed knowledge of cancer signalling pathways gained so far - particularly from highthroughput genomic and proteomic techniques - unravels the complexity of processes controlling cancer initiation and progression. However, despite certain advances in cancer therapy, the translational impact of this enormous wealth of knowledge mostly stayed behind the high-flying expectations of the post-genomic era. Today, the challenges for future anticancer treatments are evident, and need to be met by scientific breakthroughs. In bridging the so-called innovation gap, pharma industry more and more relies on academia. Therefore, we aim to provide a platform for sharing newest results in cancer signalling, and are extremely happy to bring together leading experts from all over the world. Our agenda for the next days is rich of scientific top class presentations but also leaves room for informal gatherings and social activities. We hope that this will fuel productive interactions between scientists of different disciplines and generations. In particular, we would like to encourage young scientists to seize the opportunity to approach senior researchers and journal editors for questions related to their research, publishing and scientific careers. Finally, we would like to thank you all for your participation and contribution to this meeting. We are overwhelmed by the great response to the conference announcement and the high quality of abstract submissions. We are very much looking forward to an exciting meeting. Ivan Đikić, Margaret Frame and René Medema 4

6 II - PRACTICAL ISSUES Registration desk opening: Friday, May 23 rd : 15:00 18:00 Saturday, May 24 th : 8:00 9:00 and during tea breaks Sunday, May 25 th Tuesday 27 th : during tea breaks Requests can also be sent at any time by to We will try to respond to any inquiry as soon as possible. Moreover, you can always approach the hotel reception. Issues related to the conference will be forwarded to us. Badges We kindly ask you to wear your conference badge visibly throughout the meeting. Lecture hall The oral sessions take place in the main congress hall Ragusa (R level). File transfer for oral presentations We would like to ask all speakers to approach the technical personnel in the lecture hall during one of the tea breaks before the start of the assigned session in order to transfer the presentation to the local computer. Please take the time to check whether your presentation works as expected and no data has been lost during the transfer. Poster mounting The poster sessions take place in front of the Bobara Hall (5 th floor). Each presenter will be assigned a poster board and mounting pins. The board will indicate the poster number in the upper right or left corner. Authors are responsible for mounting their posters the morning of their session and removing them as the session ends. Vouchers for meals and excursion At the registration desk you have been handed out vouchers for meals and the excursion on Sun, 25 th May. Please make sure to carry them with you when attending the dinners and for the excursion. The hotel personnel will collect these vouchers from you in the restaurant and at the meeting point of the excursion, respectively. 5

7 Excursion On Sun, 25th May we have organised a boat trip to Dubrovnik followed by a guided tour through the historical centre of Dubrovnik and a visit of the Rector Palace. The evening is at your own disposal. We have arranged a bus transfer back to the Hotel. For those who would like to spend the evening in Dubrovnik the busses depart from plateau PILE (western entrance to the city) at and Participants who would like to return to the Hotel earlier can take the bus departing from Hotel Excelsior directly after the city tour. Meeting point and departure: Hotel lobby at (on Sun, 25 th May) Please indicate your preferred return time in the lists displayed at the registration desk till noon on Sat, 24 th May. Poster Prizes We are glad to announce that there will be five poster prizes awarded to the best poster presentations. Besides the content of the poster (i.e. originality, coherency, presentation of key messages and data, alignment with abstract) special attention will be given to the communicative skills of the presenter. The prizes will be handed over during the closing ceremony on Tuesday, 27 th May. Two poster prizes ( 250 each) are funded by the European Association for Cancer Research. Two further poster prizes are funded by The EMBO Journal and EMBO reports, both comprising of vouchers in the amount of 200 each, to be redeemed in any EMBO course, workshop, conference or practical course. One prize is sponsored by Nature Reviews cancer and includes a year s personal subscription to Nature Reviews Cancer. Venue Hotel Croatia Cavtat Frankopanska Cavtat-Dubrovnik, Croatia Tel: or Fax:

8 III - SPONSORS 23rd 27th May, 2014, Cavtat, Croatia 7

9 Programme Friday, May 23, 2014 IV - PROGRAMME in Ragusa Hall Friday May 23, 2014 Chair: Ivan Dikic Arrival and registration Welcome words Ivan Dikic, Goethe University Frankfurt, Germany Keynote lecture: Seven Transmembrane Receptors Robert Lefkowitz, Duke University, USA Keynote lecture: Cell signalling by receptor tyrosine kinases: from basic principles to cancer therapy Joseph Schlessinger, Yale University, USA Keynote lecture in Memory of Tony Pawson Guiding Signals through Anchored Enzyme Complexes John Scott, University of Washington, USA KL01 KL02 KL03 20:15 Welcome dinner Restaurant Alverde Terrace 8

10 Programme Saturday, May 24, 2014 Saturday May 24, 2014 Session I Oncogenic signalling networks I Chair: John Scott Keynote lecture: Targeting K- Ras driven tumors Mariano Barbacid, Centro Nacional de Investigaciones Oncológicas (CNIO), Spain Tyrosine kinase signalling networks in human cancer Roger Daly, Monash University, Australia KL04 L Ubiquitin dependent regulation of MEKK2/3- MEK5- ERK5 L06 signalling module by IAPs Krishna Rajalingam, Mainz University, Germany Tea break Piano Bar Terrace Novel targets of Raf in tumorigenesis Manuela Baccarini, Max F. Perutz Laboratories (MFPL), Austria BRAF and RAS signalling in melanoma: basic biology and therapeutic options Richard Marais, Cancer Research UK Manchester Institute, UK Increased nanoclustering as a novel mechanism for cancer associated Ras mutations Maja Solman, Turku Centre for Biotechnology, Åbo Akademi, Finland Akt can promote cancer cell survival independently of kinase activity Igor Vivanco, Institute of Cancer Research, Sutton, UK Development of an IGF2 super- antagonist by directed evolution of IGF2R Susana Frago, University of Oxford, UK L07 L08 ST01 ST02 ST Lunch break Restaurant Cavtat 9

11 Programme Saturday, May 24, 2014 Session II Genomic integrity in cancer Chair: Ruth Palmer Keynote lecture: Histidine phosphorylation: the invisible phosphoproteome? Tony Hunter, Salk Institute Cancer Center, USA KL Dynamic Re- Wiring of Signaling Networks in the DNA Damage L10 Response Using Systems Biology to Optimize Cancer Treatment Mike Yaffe, Massachusetts Institute of Technology, USA Comprehensive genomic analysis of human tumors identifies oncogenic drivers Somasekar Seshagiri, Genentech, USA L Tea break Piano Bar Terrace Control of DNA repair activity at mammalian telomeres Jacqueline J. Jacobs, Netherlands Cancer Institute, The Netherlands Signalling a cell cycle exit after radiation therapy René Medema, Netherlands Cancer Institute, The Netherlands L12 L A syndrome with early- onset hepatocellular carcinoma, instability ST04 and progeroid features is caused by mutations in DVC1/SPRTN Janos Terzic, University of Split, Croatia Balance BRCA1 and 53BP1 at DNA damage sites for DNA repair ST05 pathway choice and cancer therapy Junjie Chen, The University of Texas MD Anderson Cancer Center, USA Insights into Ribonucleotide Reductase (RNR) regulation during ST06 cell cycle progression and DNA damage response Vincenzo D'Angiolella, University of Oxford/Gray Institute, UK Poster session I Bobara Hall/ Quite Salon Fingerfood dinner 10

12 Programme Sunday, May 25, 2014 Sunday May 25, 2014 Session III Oncogenic signalling networks II Sponsored by the LOEWE project: Ub- Net Chair: Manolis Pasparakis Keynote lecture: Survival and Vascular Co- option of Metastasis Initiating Cells Joan Massague, Memorial Sloan Kettering Cancer Center, USA KL Evading the anti- tumor immune response a novel role for L15 Focal Adhesion Kinase Margaret Frame, Edinburgh University, UK Targeting Signal Transduction for the Treatment of Acute Myeloid Leukemia Hubert Serve, Goethe University Frankfurt, Germany L Tea Break Piano Bar Terrace Rap signalling complexes: landmark recognizing modules in cell adhesion and polarity Hans Bos, Utrecht University, Netherlands Tumor Suppressor role for the deubiquitinase, BAP1 Vishva Dixit, Genentech, USA L17 L OTUB1 enhances TGFβ signalling by inhibiting the ST07 ubiquitylation and degradation of active SMAD2/3 Lina Herhaus, University of Dundee, UK OncoMD: A powerful genomic data interpretation tool to make clinical decisions in cancer Amitabha Chaudhuri, MedGenome Inc., USA ST Poster session II Bobara Hall/ Quite Salon Fingerfood lunch Excursion (Dinner not included) 11

13 Programme Monday, May 26, 2014 Monday May 26, 2014 Session IV Inflammation and cancer Chair: Rene Medema Keynote lecture: Regnase- 1- mediated regulation of the immune response Shizuo Akira, Osaka University, Japan IKK/NF- kb signalling in inflammation and cancer Manolis Pasparakis, University of Cologne, Germany Loss of NF- kb1 causes gastric cancer via cytokine mediated chronic inflammation Lorraine O Reilly, The Walter and Eliza Hall of Medical Research, Melbourne, Australia KL19 L20 ST Targeting lysosomal adaptor complexes during cancer progression ST10 David McEwan, Goethe University Frankfurt, Germany Tea break Piano Bar Terrace The EGFR - exploring the unexpected Maria Sibilia, Medical University of Vienna, Austria L A Numb/p53 circuitry couples control of replicative self- renewal L22 and tumour suppression in normal and cancer mammary epithelial cells Pier Paolo Di Fiore, Istituto FIRC di oncologia molecolare (IFOM), Italy Molecular basis for engineering myeloid suppressors Peter Murray, St. Jude Children's Research Hospital, USA L Lunch Restaurant Cavtat Session V Oncology pathways in cancer metabolism and development Chair: Margaret Frame Keynote lecture: Signalling in wound- induced skin cancer Fiona Watt, University of Cambridge, UK Anaplastic Lymphoma Kinase signalling in Drosophila and mouse models Ruth Palmer, Umeå University, Sweden KL24 L Tea break Piano Bar Terrace Structural regulation of ubiquitin pathways Brenda Schulman, St. Jude Children's Research Hospital, USA Mitotic Wnt signalling regulates cell growth and proliferation Christof Niehrs, Institute for Molecular Biology (IMB), Germany L26 L27 12

14 Programme Monday, May 26, The function of p63 and p73 in genetic quality control and cancer development Volker Dötsch, Goethe University Frankfurt, Germany L Poster session III Bobara Hall/ Quite Salon Farewell dinner Spinaker Restaurant Terrace Dancing Night Club Poseidon 13

15 Programme Tuesday, May 27, 2014 Tuesday May 27, 2014 Session VI Cell death and autophagy pathways Chair: Maria Sibilia Keynote Lecture: Life and Death Decisions: Annexin AI expressed KL29 on apoptotic cells downregulates the immune response Peter Krammer, German Cancer Research Center (DKFZ), Germany Caspase- 2 as a tumour suppressor Sharad Kumar, Centre for Cancer Biology (CCB), Australia 10:15-10:25 Pushing Myc inhibition towards the clinic using a directly- deliverable cell- penetrating peptide Marie- Eve Beaulieu, Vall d'hebron Institute of Oncology, Spain L30 ST Tea break Piano Bar Terrace Keynote lecture: Autophagy in cancer Yoshinori Ohsumi, Tokyo Institute of Technology, Japan Autophagy in haematological tumors Katharina Simon, University of Oxford, UK Autophagy: Friend or foe in the treatment of fusion protein- associated leukemias? Anne Simonsen, University of Oslo, Norway Salmonella drives cellular transformation and cancer Tiziana Scanu, The Netherlands Cancer Institute (NKI- AVL), NL KL31 L32 L33 ST Poster award ceremony and closing remarks Lunch Restaurant Cavtat Departure 14

16 ABSTRACTS Welcome session Friday, May 23, 2014 Welcome session KL01 V - ABSTRACTS 1) Oral presentations Seven Transmembrane Receptors Robert Lefkowitz Howard Hughes Medical Institute, Duke University Medical Center, Durham, USA Seven transmembrane receptors (7TMRs), also known as G protein coupled receptors (GPCRs) represent by far the largest, most versatile, and most ubiquitous of the several families of plasma membrane receptors. They regulate virtually all known physiological processes in humans. As recently as 40 years ago, the very existence of cellular receptors for drugs and hormones was highly controversial, and there was essentially no direct means of studying these putative molecules. Today, the family of GPCRs is known to number approximately 1,000, and crystal structures have recently been solved of approximately 20 members of the family and even of a receptor-g protein complex. In my lecture, I will briefly review how the field has evolved over the past 40 years, hanging some of the story on my own research throughout this period. Then I will discuss recent developments in the field, which are changing our concepts of how the receptors function and are regulated in fundamental ways. Finally, I will discuss the possibility of leveraging this new mechanistic and molecular information to develop new classes of therapeutic agents. 15

17 ABSTRACTS Welcome session Friday, May 23, 2014 KL02 Cell signalling by receptor tyrosine kinases; from basic principles to cancer therapy Joseph Schlessinger Yale University School of Medicine, Department of Pharmacology, New Haven, USA Receptor tyrosine kinases (RTKs) comprise a family of cell surface receptors that control many critical cellular processes. Various human diseases are caused by dysfunction in RTKs or in their intracellular signalling pathways. Most RTK are expressed on the cell membrane as inactive monomers that upon ligand stimulation undergo receptor dimerization. RTK dimerization is necessary for kinase activation and tyrosine autophosphorylation; both processes are mediated by an intermolecular mechanism. While dimerization is essential for activation of all RTK different members of the RTK family utilize different mechanisms for maintaining monomeric RTKs in inactive autoinhibited configuration and utilize alternative mechanisms for ligand dependent dimerization and activation. Mechanism that governs autoinhibition and ligand induced activation of members of Type I RTK including EGF-receptor, ErbB2 and ErbB3 will be described. Moreover the mode of action of novel therapeutic antibodies that target members of Type I RTKs will be presented. Stem Cell Factor (SCF) initiates its multiple cellular responses by binding to the extracellular region of the RTK KIT resulting in receptor dimerization and tyrosine kinase activation. We have determined the crystal structure of the entire extracellular region of KIT before and after SCF stimulation. The structures show that KIT dimerization is driven by SCF binding whose sole role is to bring two KIT molecules together. We have used X-ray crystallography, electron microscopy (EM) and biochemical experiments to determine the three dimensional structure of intact, SCF-stimulated KIT dimers. Several forms of dimeric KIT molecules with different asymmetric arrangements of the two tyrosine kinase domains were identified. These asymmetric contacts may represent specific interactions occurring between two KIT tyrosine kinase domains poised towards trans autophosphorylation. We propose that cooperative interactions mediated by multiple weak homotypic contacts between the extracellular, transmembrane and cytoplasmic regions of KIT are responsible for tyrosine kinase activation and cell signalling in normal and transformed cells. 16

18 ABSTRACTS Welcome session Friday, May 23, 2014 KL03 Guiding Signals through Anchored Enzyme Complexes John Scott HHMI/University of Washington, Seattle, USA Intracellular signal transduction events are precisely regulated in space and time. This is achieved in part by A-Kinase Anchoring Proteins (AKAPs) that tether signalling enzymes such as protein kinases and phosphatases in proximity to selected substrates. AKAP targeting provides an efficient means to reversibly control the phosphorylation status of key substrates and contributes to the dynamic regulation of sophisticated cellular events. Using a variety of genetic, electrophysiological and live-cell imaging techniques we show that AKAPs, which enhance the precision of signalling events, are up-regulated under certain pathophysiological states. This leads to aberrant regulation of certain physiological processes and disorders such as diabetes and heart disease. In this talk I will present some recent data on the role of anchored signalling complexes that modulate various extra-pancreatic complications of diabetes including hypertension and cataract formation. 17

19 ABSTRACTS Oncogenic signalling neworks I Saturday, May 24, 2014 Session I: Oncogenic Signalling networks I KL04 Targeting K-RAS driven tumors Mariano Barbacid Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain K-RAS oncogenes have been implicated in about one fifth of all human cancers including those with the worse prognosis including lung adenocarcinoma, a type of non-small cell lung carcinoma (NSCLC), and pancreatic ductal adenocarcinoma (PDAC). We have developed genetically engineered mouse (GEM) strains that closely recapitulate the natural history of these human neoplasias. We have used these strains to validate targets of potential therapeutic value with the ultimate goal to translate these findings to the clinic. Briefly, we have crossed these GEM strains with mice that carried conditional knock out mutations in loci encoding potential therapeutic targets. These targets were ablated by genetic means (using inducible recombinases) either at the time of tumor initiation or, whenever possible, once the tumor has been generated. Then, we follow the fate of the tumor in the absence of the target. This genetic-based strategy has significant advantages over classical pharmacological studies since it does not rely on the quality of the drug/inhibitor. For instance, the observed effects are always mechanism-based and not offtarget effects. Moreover, if the target is eliminated systemically, our studies offer relevant information regarding potential toxic effects that may occur when the target would be pharmacologically inhibited in normal tissues. More recently, we are replacing the conditional knock strains by conditional knocked in mice so we can express kinase dead isoforms instead of eliminating the target. We hope that this experimental approach will mimic more accurately those pharmacological responses that will be observed in the clinic. Using these experimental approaches, we have validated each of the K-Ras downstream kinases including those of the Raf/Mek/Erk pathway as well as the cell cycle Cdks. Our results have revealed some unexpected results which may have important implications for the development of future targeted therapies. For instance. we have established that whereas c-raf is essential for the development of lung adenocarcinomas and pancreatic ductal adenocarcinomas, the closely related B-Raf and A-Raf kinases are completely dispensable, indicating that these enzymes do not have compensatory activities in tumor development, as previously thought. Likewise, lung adenocarcinomas do not progress in the absence of Cdk4. However, ablation of the highly related cell cycle kinases Cdk2 and Cdk6 have no significant effect on tumor development. These observations underscore the need to carry out target validation studies using mouse models in order to design selective therapies that will have a greater chance of success in the clinic. Finally, we have also validated some upstream signalling effectors, mainly the EGF receptor for which there are already selective inhibitors. Unexpectedly, whereas ablation of EGF receptors has no therapeutic value in K-Ras driven lung adenocarcinomas and intestinal tumors (as previously observed in the clinic), it is essential for the initiation of pancreatic tumors. These findings indicate that K-Ras oncogenic signalling proceeds through different effector pathways in a tumor specific manner, an observation that should also help to design more selective therapies. 18

20 ABSTRACTS Oncogenic signalling neworks I Saturday, May 24, 2014 L05 Tyrosine kinase signalling networks in human cancer Roger J. Daly Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia The human genome encodes 518 protein kinases, collectively referred to as the kinome. This enzyme superfamily harbours considerable untapped potential in terms of cancer drug targets and biomarkers. In addition, it is evident that many kinases implicated in cancer development remain poorly characterized. We propose that this knowledge gap can be bridged by an integrated strategy that combines mass spectrometry (MS)-based phosphoproteomic and kinomic profiling with functional genomics. This provides the analytical power to identify kinome pertubations characteristic of a particular oncogenic event and functionally annotate the identified kinase network. The tyrosine kinase and proto-oncogene product Src plays a key role in major human cancers such as those of the breast and colon, and is the target of small molecule tyrosine kinase inhibitors currently in clinical development. We have used phosphoproteomic profiling to identify the pseudokinase SgK269 as a novel target of Src family kinases. Characterization of SgK269 determined that it functions as a scaffold, playing a key role in temporal and qualitative control of growth factor receptor signal output, and also acts as a breast cancer oncogene. Our recent work demonstrates that the SgK269 interactome is complex and includes the related pseudokinase SgK223, as well as specific proteins that regulate the degradation of SgK269. In order to determine the global impact of active Src on the kinome we have established a novel kinase capture platform and used this in combination with quantitative MS-based proteomics to characterize alterations in kinase expression and/or activation that occur in MCF-10A mammary epithelial cells expressing active Src. This has identified ~ 100 kinases that change in expression/activation, including many that are poorly characterized and that do not have known links to Src-mediated transformation. Functional annotation of this Src-regulated kinome is being undertaken by sirna screens in 2D and 3D culture. 19

21 ABSTRACTS Oncogenic signalling neworks I Saturday, May 24, 2014 L06 Ubiquitin dependent regulation of MEKK2/3-MEK5-ERK5 signalling module by IAPs Krishnaraj Rajalingam Institute of Biochemistry II, Goethe University, Frankfurt, Germany Mitogen activated protein kinases (MAPKs) are highly conserved protein kinase modules and they control fundamental cellular processes. While the activation of MAPKs has been well studied, little is known on the mechanisms driving their inactivation. Here we uncover a role for ubiquitination in the inactivation of a MAPK module. Extracellular-signal-Regulated Kinase 5 (ERK5) is a unique, conserved member of the MAPK family and is activated in response to various stimuli through a three-tier cascade constituting MEK5 and MEKK2/3. We reveal an unexpected role for Inhibitors of Apoptosis Proteins (IAPs) in the inactivation of ERK5 pathway in a bimodal manner involving direct interaction and ubiquitination. XIAP directly interacts with MEKK2/3 and competes with PB1 domain-mediated binding to MEK5. XIAP and ciap1 conjugate K63-linked ubiquitin chains to MEKK2 and MEKK3 which directly impedes MEK5- ERK5 interaction in a trimeric complex leading to ERK5 inactivation. Consistently, loss of XIAP or ciap1 by various strategies leads to hyperactivation of ERK5 in normal and tumorigenic cells. Loss of XIAP promotes differentiation of human primary skeletal myoblasts to myocytes in a MEKK2/3-ERK5 dependent manner. Our results reveal a novel, obligatory role for IAPs and ubiquitination in the functional disassembly of ERK5-MAPK module and human muscle cell differentiation. 20

22 ABSTRACTS Oncogenic signalling neworks I Saturday, May 24, 2014 L07 Novel targets of Raf in tumorigenesis Anna Lina Cavallo, Ines Jeric, Gabriele Maurer, Manuela Baccarini University of Vienna, Center of Molecular Biology, Max F. Perutz Laboratories, Vienna, Austria The Baccarini lab uses conditional ablation to investigate the essential functions of ERK pathway components in vivo and in cultured cells. This strategy has lead to the discovery of unexpected cross talk between Raf and other pathways, particularly those that control the cytoskeleton. These interactions affect both the tumor itself and its vasculature, promoting tumorigenesis. We will discuss how, in a specific setting, C-Raf operates as a tumor suppressor instead, and the mechanisms underlying this unexpected function. 21

23 ABSTRACTS Oncogenic signalling neworks I Saturday, May 24, 2014 L08 BRAF and RAS signalling in melanoma: basic biology and therapeutic options Richard Marais The CRUK Manchester Institute, Manchester, UK The small G-protein NRAS is mutated in ~20% of melanomas and its downstream effector, the protein kinase BRAF is mutated in another ~40% of cases. NRAS and BRAF are components of a conserved signalling module that controls cell growth and differentiation and mutant NRAS and BRAF drive constitutive signalling through this pathway. We have developed mouse models of melanoma driven by oncogenic BRAF or NRAS. Curiously, the BRAF mice develop cutaneous melanoma, whereas the NRAS mice develop melanoma of the CNS, but only when the oncogenic NRAS is expressed during embryogenesis. Our models show that although both BRAF and NRAS can be initiating events in melanoma, by themself these oncogenes are insufficient to drive melanoma and other genetic events are required. We are currently using these mice to study the gene-gene and gene-environment interactions that drive melanomagensis. Critically, drugs that target BRAF block pathway signalling in BRAF-mutant melanoma, extending both progression-free and overall survival in patients. However, when cells carry an NRAS mutation, BRAF inhibitors drive an unexpected paradox, and stimulate pathway activity. This is because when RAS is activated, BRAF inhibitors drive the formation of hetero and homo-dimers between BRAF and a closely related protein called CRAF. These dimers contain a drug-bound and a drug-free partner and the drug-bound partner activates the drug-free partner by trapping it at the plasma membrane where it is activated, or by inducing an activating conformational change. Critically, this paradox stimulates the development of secondary tumours in patients being treated for BRAF-mutant melanoma by driving the growth of pre-existing but previously benign lesions carrying mutations in RAS. We have also discovered that the paradox drives invasion and metastasis in RAS mutant melanoma cells and in BRAF mutant cells that develop resistance to BRAF inhibitors, findings that have clear clinical implications. 22

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