Dr. Ian Watson
Rosalind and Morris Goodman Cancer Research Centre
Department of Biochemistry
Melanoma is the deadliest form of skin cancer. Detected in its earliest stages, melanoma is highly curable; however, the 5-year survival rate declines drastically for regional and distant metastatic disease. Recently, melanoma has emerged as the latest success story for both genomics- and immune-guided targeted therapy. Cutaneous melanoma is characterized by hotspot mutations in the mitogen-activated protein kinase (MAPK) regulators, BRAF and NRAS, found in approximately 50% and 25% of patients, respectively. The identification of these oncogenic mutations has led to the development of small molecule inhibitors targeting MAPK kinase kinases (MEK) and BRAF in melanoma. Although antitumor responses to MAPK targeted therapies have been dramatic, they are rarely durable. Furthermore, novel therapies targeting inhibitory immune checkpoint proteins have recently shown impressive clinical efficacy; nevertheless, biomarkers that predict response remain unclear.
For the past four years, I have led a number of multi-institutional collaborations (Hodis, Watson et al., 2012 Cell), which include The Cancer Genome Atlas project (TCGA, 2015 Cell), to characterize the melanoma genome and perform integrative analysis with multiple data platforms at the DNA, RNA, and protein levels. Our work has identified a number of novel significantly mutated genes in melanomas, which possess hotspot mutations in coding and non-coding regions. Based on the frequency and correlation of the most frequently significantly mutated genes, we established a framework for genomic classification into one of four subtypes: mutant BRAF, RAS, NF1, and Triple-WT (wild-type) melanomas.
In an attempt to improve on the current diagnostic and treatment modalities employed in the clinic, my lab will address the following questions:
- What is the biological function and therapeutic relevance of novel significantly mutated genes discovered in our melanoma genome- and exome-sequencing studies?
- How can we target melanomas lacking BRAF and RAS hotspot mutations and prioritize such strategies in the context of immunotherapies?
- What are the mechanisms that mediate response and resistance to MAPK-targeted and immunotherapy?
To tackle these problems, my lab will employ computational approaches, in vivo models and biochemical techniques studying patient samples, cell lines, and melanoma mouse models.
1. Cancer Genome Atlas Research Network (Watson IR*).Comprehensive Genomic Characterization of Cutaneous Melanoma. Cell. 2015 Jun 18;161(7):1681-96.
*Project co-Chair and co-corresponding author
- Watson IR*, Li L*, Cabeceiras PK, Mahdavi M, Gutschner T, Genovese G, Wang G, Fang Z, Tepper JM, Stemke-Hale K, Tsai KY, Davies MA, Mills GB, Chin L. The RAC1 P29S Hotspot Mutation in Melanoma Confers Resistance to Pharmacological Inhibition of RAF. Cancer Research. 2014 Sep 1;74(17):4845-52.
Yen J, White RM, Wedge DC, Van Loo P, de Ridder J, Capper A, Richardson J, Jones D, Raine K, Watson IR, Wu CJ, Cheng J, Martincorena I, Nik-Zainal S, Mudie L, Moreau Y, Marshall J, Ramakrishna M, Tarpey P, Shlien A, Whitmore I, Gamble S, Latimer C, Langdon E, Kaufman C, Dovey M, Taylor A, Menzies A, McLaren S, O Meara S, Butler A, Teague J, Lister J, Chin L, Campbell P, Adams DJ, Zon LI, Patton EE, Stemple DL, Futreal PA. The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models. Genome Biology. 2013 Oct 23;14(10):R113.
Braeuer RR, Watson IR, Wu CJ, Mobley AK, Kamiya T, Shoshan E, Bar-Eli M. Why is melanoma so metastatic? Pigment Cell Melanoma Research. 2014 Jan;27(1):19-36.
Watson IR, Takahashi K, Futreal PA, Chin L. Emerging patterns of somatic mutations in cancer. Nature Review Genetics. 2013 Oct;14(10):703-18.
Hodis E*, Watson IR*, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, Dicara D, Ramos AH, Lawrence MS, Cibulskis K, Sivachenko A, Voet D, Saksena G, Stransky N, Onofrio RC, Winckler W, Ardlie K, Wagle N, Wargo J, Chong K, Morton DL, Stemke-Hale K, Chen G, Noble M, Meyerson M, Ladbury JE, Davies MA, Gershenwald JE, Wagner SN, Hoon DS, Schadendorf D, Lander ES, Gabriel SB, Getz G, Garraway LA, Chin L. A landscape of driver mutations in melanoma. Cell. 2012 Jul 20;150(2):251-63.
Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, Ivanova E, Watson IR, Nickerson E, Ghosh P, Zhang H, Zeid R, Ren X, Cibulskis K, Sivachenko AY, Wagle N, Sucker A, Sougnez C, Onofrio R, Ambrogio L, Auclair D, Fennell T, Carter SL, Drier Y, Stojanov P, Singer MA, Voet D, Jing R, Saksena G, Barretina J, Ramos AH, Pugh TJ, Stransky N, Parkin M, Winckler W, Mahan S, Ardlie K, Baldwin J, Wargo J, Schadendorf D, Meyerson M, Gabriel SB, Golub TR, Wagner SN, Lander ES, Getz G, Chin L, Garraway LA. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature. 2012 May 9;485(7399):502-6.