RAS and RAF Signalling in Melanoma: Biology and Therapies Professor Richard Marais
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1 RAS and RAF Signalling in Melanoma: Molecular Oncology, The Institute of Cancer Research, UK 1 Melanoma Melanocytes are specialised pigment cells - Skin, eyes, ear, brain, heart - Skin/hair tone - Protection from UV radiation (tanning response) - Precursors of melanoma Melanoma: the most deadly skin cancer - 10% of all skin cancers, but 80% of skin cancer deaths - Europe: over 62,000 cases pa; ~12,000 deaths - 80% are cured by surgery; 20% die of metastatic disease - Median survival: 6-9 months; 5 year survival: 5-10% - Risk factors: UV light/genetics 2 ERK signalling in melanoma CKIT: 5% (mucosal, RTKacryl) NRAS: 22% KRAS: 2% HRAS: 1% (cutaneous) GNAQ: 5% (uveal) GPCR RAS α β γ RAF BRAF: 44% (cutaneous) MEK ERK Hyper-activated in over 90% 3 The screen versions of these slides have full details of copyright and acknowledgements 1
2 BRAF transforms melanocytes ERK signalling Soft agar growth Parental Vector WT BRAF BRAF Myc-tag BRAF ppmek pperk MEK ERK BRAF Wellbrock et al., 2004 Cancer research 4 Mouse models of melanoma Express oncogene in a tissue specific manneri.e., melanocytes Express oncogene at normal physiological levels Expression should be regulated to mimic its acquisition in humans 5 BRAF inducible mouse loxp loxp loxp Braf prom. Ex1 Ex2 Ex Term Neo R 15 Tyr. Enh. Tyr. prom. Cre recombinase ERT2 4-OHT loxp Braf prom. Ex1 Ex2 Ex The screen versions of these slides have full details of copyright and acknowledgements 2
3 BRAF induces skin hyper-pigmentation 7 BRAF induces senescence in melanocytes Ki months after BRAF 19 months after BRAF SA-β-Gal WT skin Nevus p16 Gapdh 8 BRAF induces melanoma Ki-67 * S100 * * 9 The screen versions of these slides have full details of copyright and acknowledgements 3
4 Tumour cells have metastatic potential Cells grow as tumours in lungs Desmoplastic margins Control Cells Weight (g) PBS Cells Lungs PBS Cells 10 Role of p16 INK4a? Over 50% of human tumours have lost the tumour suppressor p16 INK4a umour free % tu controls p16 INK4a WT p16 INK4a null p16 Gapdh Nevi Tumour Tumour Liver WT skin Time (months) p16 -/- p16 +/+ p16 -/- 11 BRAF mutations in cancer CR1 CR2 kinase Wan et al., 2004 Glycine-rich loop Activation segment 12 The screen versions of these slides have full details of copyright and acknowledgements 4
5 Most mutants are active Wan et al., 2004 G469A E586K V600D V600K V600R K601E 13 Impaired activity mutants: activate ERK through CRAF BRAF activity CRAF activity G466V G466V H1666 cells ( G466V BRAF) Wan et al., 2004 Garnett et al., Kinase-dead mutants don t appear to signal Xenopus oocytes BRAF CRAF G466V G466V 15 The screen versions of these slides have full details of copyright and acknowledgements 5
6 BRAF mutants have different modes of action Impaired activity mutants BRAF* CRAF Activated mutants (high/intermediate) BRAF* MEK ERK Kinase-dead mutants BRAF*? Wan et al., 2004 Garnett et al., 2005 Adapted from Garnett and Marais, BRAF mutations in cancer ~11,000 mutations in BRAF in cancer No coincidence with RAS mutations 32 D594 mutations in BRAF in cancer 3 are coincident with KRAS mutations (G12/G13) 1 is coincident with an NRAS mutation (Q61) Highly significant enrichment p< 10-7 Suggests a functional interaction between kinase-dead BRAF and oncogenic RAS? 17 Conditional kinase-dead BRAF and oncogenic KRAS mice Braf prom. loxp Ex14 MG loxp D594A stop 15 Kras prom. Ex1 G12D loxp loxp stop 2 Tyr. Enh. Tyr. prom. Cre recombinase ERT2 4-OHT loxp D594A loxp G12D Braf prom. Ex14 15 Kras prom. Ex The screen versions of these slides have full details of copyright and acknowledgements 6
7 D594A BRAF and G12V KRAS cooperate to induce melanoma of Proportion tumour-free mice (%) 19 PD (PD): MEK inhibitor (CI1040) Sorafenib (SF): BRAF, CRAF and other kinases 885-A: BRAF selective (analogue or SB590885) PLX4720 (PLX): BRAF selective The screen versions of these slides have full details of copyright and acknowledgements 7
8 BRAF is inert in RAS mutant melanoma cells (NRAS) (BRAF) Dumaz et al., 2005 A375 (BRAF) D04 (NRAS) 22 CRAF and RAS are required D04 (NRAS mutant cells) 23 RAF inhibitors induce CRAF binding to BRAF in RAS mutant cells D04 (NRAS) WM852 (NRAS) A375 ( BRAF) 24 The screen versions of these slides have full details of copyright and acknowledgements 8
9 RAS binding is required 25 BRAF inhibitors recruit BRAF to the membrane 17% 34% 44% 49% 26 Growth factors induce BRAF-CRAF complexes and sustained signalling 27 The screen versions of these slides have full details of copyright and acknowledgements 9
10 Gatekeeper mutants 28 Kinase-dead BRAF binds to CRAF & activates MEK Similar results with K483M BRAF and D594V BRAF The screen versions of these slides have full details of copyright and acknowledgements 10
11 Sorafenib induced paradoxical CRAF activation Sorafenib is a pan-raf inhibitor that may inhibit CRAF 31 T421N CRAF converts Sorafenib to a pathway activator pperk 32 Pan-RAF inhibitors induce paradoxical CRAF activity 33 The screen versions of these slides have full details of copyright and acknowledgements 11
12 34 BRAF mutants have different modes of action Impaired activity mutants BRAF* CRAF Activated mutants (high/intermediate) BRAF* MEK ERK Kinase-dead mutants RAS* BRAF* CRAF Wan et al., 2004 Garnett et al., 2005 Adapted from Garnett and Marais, The screen versions of these slides have full details of copyright and acknowledgements 12
13 37 Conclusions BRAF can be a founder event in melanomagenesis BRAF is a validated therapeutic target BRAF drugs are effective in patients BRAF inhibition activates MEK through CRAF when RAS is mutated Kinase-dead BRAF and oncogenic RAS cooperate to induce melanoma What of other tumours; other kinases; pseudo-kinases BRAF-selective drugs: Should not be used in RAS mutant tumours (use pan-raf, CRAF drugs or combinations) Theoretical risk of tumour progression if RAS mutations are acquired Theoretical risk of tumour promotion in other tissues 38 Signal transduction team Imanol Arozarena (Spain) Nathalie Dhomen (The Netherlands) Tessa Gaarenstroom (The Netherlands) Robert Hayward (UK) Sonja Heidorn (Germany) Ruth Kirk (UK) Matthew Martin (Canada) Carla Milagre (Portugal) Leisl Packer (Australia) Malin Pedersen (Sweden) Joel Rae (UK) Sareena Rana (The Netherlands) Ana Rebocho (Portugal) Berta Sanchez-Laorden (Spain) Samra Turajlic (Bosnia) Amaya Viros (Spain) Steven Whittaker (UK) Neus Cantarino (Spain) Vicky Emuss (UK) Silvy da Rocha-Diaz (Canada) Gene and Oncogene Targeting Team Caroline Springer Structural biology team David Barford Molecular pathology team Jorge Reis-Filho Royal Marsden Hospital James Larkin Martin Gore CRUK-LRI Christina Hidalgo-Carcedo Erik Sahai The Harry J. Lloyd Charitable Trust Leicester University Catrin Pritchard Institut Curie, Paris Veronique Delmas Lionel Larue 39 The screen versions of these slides have full details of copyright and acknowledgements 13
14 40 The screen versions of these slides have full details of copyright and acknowledgements 14
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