The Molecular Oncology laboratory investigates oncogenes as therapeutic targets for cancer.
By targeting oncogenic signalling in cancer and understanding the impact of this therapy on both the tumour cell and its microenvironment, we aim to develop novel treatment strategies that are durable and prevent therapy resistance. The McArthur laboratory has a specific interest in melanoma, but also investigates ovarian, lung, colorectal and haematological cancers.
Targeting CDK4 in melanoma
Melanoma treatment is undergoing a fundamental change due to the success of both BRAF targeted and immune therapies; however, both have their limitations. Typically, targeted therapies are associated with short-term responses due to acquisition of therapy resistance in patients; in contrast, immunotherapies have a lower patient response rate, but have long-term responses.
In preclinical studies using melanoma cell lines and in vivo models, we have demonstrated remarkably prolonged responses to a combination of targeted inhibitors to mutant BRAF and CDK4. We are now investigating how the combination of BRAF/MEK/ERK and CDK4 inhibitors induce durable responses. Furthermore, we are investigating the potential mechanism behind the development of resistance to each of these therapies. Understanding mechanisms of resistance is now an essential part of targeted therapy development, as it can provide both a biomarker for early detection of treatment failure and options for alternative subsequent treatments.
Impact of targeted therapy on the immune microenvironment
Targeted therapies can affect the tumour immune microenvironment, and understanding this is essential in advancing these agents, as well as their combination with immunotherapies, into the clinic. We have demonstrated that the synergy observed by dual targeting of the MAPK/ERK and CDK4 pathways in melanoma is due to a direct effect on the melanoma cell; however, in vivo there is also an immune component that could potentially increase the efficacy of these drug combinations.
Using melanoma cell lines, in vivo models and patient samples, we are currently investigating the direct effect of these targeted therapies on immune cell function and how these targeted therapies affect current immunotherapies. One of the ways we are doing this is using a multispectral imaging platform that can assess many cell types both within and surrounding the tumour, thus allowing us to determine the spatial relationship between these different cell types.
Metabolic reprogramming in BRAF mutant melanoma
Metabolic reprogramming is a recognised hallmark of cancer. To support continued proliferation and growth, tumour cells must metabolically adapt to balance their bioenergetic and biosynthetic needs. To achieve this, cancer cells switch from mitochondrial oxidative phosphorylation to predominantly rely on glycolysis, a process known as the Warburg effect. The BRAF oncogene, mutated in approximately 50 per cent of melanoma patients, has recently emerged as a critical regulator of this process, bringing to the fore the importance of metabolic reprogramming in the pathogenesis and treatment of melanoma.
To further explore regulation of glycolysis by BRAF, we have performed a genome-wide RNAi screen. This approach has identified a network of novel protein complexes and pathways that may play a role in coupling oncogenic BRAF signalling to metabolic reprogramming. Significantly, depletion of components of this network specifically synergise with vemurafenib to potently suppress glycolysis and survival. These novel regulators of BRAF-driven metabolic reprogramming are under further investigation, using metabolomics and Seahorse Extracellular Flux analysis, for their potential as therapeutic targets in the context of BRAF-mutant melanoma.
Targeting metabolism in RAS-driven malignancies
This project aims to understand oncogenic reprogramming of metabolism in the context of NRAS-mutant melanoma, and KRAS-mutant lung and colorectal cancer, with an emphasis on therapeutic implications. Using small molecule inhibitors, cancer cell lines are being characterised in terms of metabolic implications and therapeutic efficacy. Methodologies employed include use of the Seahorse Extracellular Flux Analyzer and high-throughput chemical screening.
Understanding the role of the MYC oncogene in malignant progression and the therapeutic inhibition of RNA Polymerase I transcription
A MYC “core” binding signature centres on ribosome biogenesis and growth; that is, those pathways most consistently MYC regulated among numerous cell-type and context-specific genome-wide studies. We are exploring the hypothesis that MYC’s oncogenicity depends largely on its ability to drive transcriptional programs, including ribosomal biogenesis, which are required to meet the bioenergetic needs of the growing and dividing cancer cell.
This work focuses on understanding how MYC regulation of these processes and the associated feedback mechanisms may sensitise MYC-driven cancers to therapeutic targeting of RNA polymerase I transcription. We are using in vivo models (such as Eμ-Myc) and genome-wide profiling techniques (ChIP-seq, 4C-seq, RNA-seq) to address the mechanistic and therapeutic interplay between MYC, malignant progression, sensitivity and subsequent acquired resistance to Pol I inhibition in various haemopoietic and solid tumour settings.
Wong SQ, Behren A, Mar VJ, Woods K, Li J, Martin C, Sheppard KE, Wolfe R, Kelly J, Cebon J, Dobrovic A, McArthur GA. Whole exome sequencing identifies a recurrent RQCD1 P131L mutation in cutaneous melanoma. Oncotarget. 2015; 6(2):1115-27.
Parmenter TJ, Kleinschmidt M, Kinross KM, Bond ST, Li J, Kaadige MR, Rao A, KE Sheppard, Hugo W, Pupo GM, Pearson RB, McGee SL, Long GV, Scolyer RA, Rizos H, Lo RS, Cullinane C, Ayer DE, Ribas A, Johnstone RW, Hicks RJ, McArthur GA. Response of BRAF mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discov. 2014; 4(4):423-33.
Young RJ, Waldeck K, Martin C, Foo JH, Cameron DP, Kirby L, Do H, Mitchell C, Cullinane C, Liu W, Fox SB, Dutton-Regester K, Hayward NK, Jene N, Dobrovic A, Pearson RB, Christensen JG, Randolph S, McArthur GA, Sheppard KE. Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines. Pigment Cell Melanoma Res. 2014; 27(4):590–600.
Ribas A, Gonzalez R, Pavlick A, Hamid O, Gajewski TF, Daud A, Flaherty L, Logan T, Chmielowski B, Lewis K, Kee D, Boasberg P, Yin M, Chan I, Musib L, Choong N, Puzanov I, McArthur GA. Combination of vemurafenib and cobimetinib in patients with advanced BRAFV600-mutated melanoma: a phase 1b study. Lancet Oncol. 2014; 15(9):954-65.
Mar VJ, Wong SQ, Li J, Scolyer RA, McLean C, Papenfuss AT, Tothill RW, Kakavand H, Mann GJ, Thompson JF, Behren A, Cebon JS, Wolfe R, Kelly JW, Dobrovic A, McArthur GA. BRAF/NRAS wild-type melanomas have a high mutation load correlating with histologic and molecular signatures of UV damage. Clin Cancer Res. 2013; 19(17):4589-98.
Wall M, Poortinga G, Stanley KL, Lindemann RK, Bots M, Chan CJ, Bywater MJ, Kinross KM, Astle MV, Waldeck K, Hannan KM, Shortt J, Smyth MJ, Lowe SW, Hannan RD, Pearson RB, Johnstone RW, McArthur GA. The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence. Cancer Discov. 2013; 3(1):82-95.
Bywater MJ, Poortinga G, Sanij E, Hein N, Peck A, Cullinane C, Wall M, Cluse L, Drygin D, Anderes K, Huser N, Proffitt C, Bliesath J, Haddach M, Schwaebe MK, Ryckman DM, Rice WG, Lowe SW, Johnstone RW, Pearson RB, McArthur GA*, Hannan RD*. Inhibition of RNA Polymerase I as a Therapeutic Strategy to promote Cancer-Specific Activation of p53. Cancer Cell. 2012; 22(1):51-65. (* Equal corresponding author)