Regulation of the oncogenic potential of signalling through the Ras/ERK pathway by dual-specificity phosphatase 5

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Abnormal activation of the Ras/ERK signalling pathway plays a causative role in disease initiation and progression and approximately one third of all human cancers exhibit mutations known to cause Ras/ERK mediated cancer formation. Furthermore, many of these cancers, such as pancreatic cancer, lung cancer and malignant melanoma have few treatment options and a poor prognosis, making this pathway an intense focus of anticancer drug development. We understand a lot about how activating mutations in ERK pathway components, such as Ras or its downstream target, Braf, cause ERK signalling to be uncontrollably "switched on" in tumours, and that such mutations can determine tumour sensitivity to anticancer drugs that inhibit the Ras/ERK pathway. In contrast, we know little about how the negative regulators of Ras/ERK signalling influence oncogenesis or drug sensitivity.We recently demonstrated that DUSP5, an inducible protein phosphatase, inhibits nuclear Ras/ERK activity and gene expression, and that deletion of DUSP5 dramatically increases mutant Ras-induced skin tumour burdens in mice, demonstrating that DUSP5 is a tumour suppressor. We therefore hypothesise that DUSP5 limits the progression of mutant Ras tumours in other tissues and in human tumours. In contrast, our more recent studies using cultured cells indicate that in the presence of Braf mutations, DUSP5 actually promotes cell growth and its deletion halts cell proliferation. We therefore hypothesise that, much like their effect on some anticancer drugs, the presence of Ras or Braf oncogenes can determine whether DUSP5 promotes or suppresses cancer cell growth. The overall objectives of this research project are two-fold:1) We will determine the effects of DUSP5 loss in clinically relevant mouse models of mutant Kras-induced cancer, namely pancreatic and lung carcinogenesis. These models closely resemble the human disease and will enable us to assess the role of DUSP5 in modulating the initiation and progression of tumours. This will be coupled with a detailed analysis of changes in ERK-dependent gene expression and signalling endpoints associated with cell proliferation, senescence, survival, migration and cell death. The latter will allow us to identify mechanism(s) and also key targets of ERK signalling involved in promoting tumour development. Finally, we will screen normal and tumour tissue samples from pancreatic cancer patients in order to assess the levels of DUSP5 and other key ERK signalling targets and to explore correlations with clinical endpoints in human disease.2) We will determine whether the role of DUSP5 in modulating the oncogenic effects of Ras/ERK signalling depends on the way in which the pathway is activated. This will be studied by monitoring the influence of DUSP5 on ERK signalling and cell fate in the presence of either Ras or Braf mutations. This has important implications for predicting how effective Ras/ERK pathway inhibitors may be in the treatment of cancer. We will therefore study the molecular mechanisms which underpin this functional difference and extend these studies to cancer cell lines in which Ras or Braf are mutant and determine if DUSP5 expression affects sensitivity either acute or chronic exposure to Ras/ERK inhibitors in clinical use. Overall, this work will inform us about DUSP5 function in the regulation of Ras/ERK signalling as it relates to cancer initiation and development, will shed light on the relative importance of the Ras/ERK pathway and its targets in cancers driven by mutant Kras and allow us to explore their clinical relevance. Finally, the idea that the role of DUSP5 in regulating ERK may become more important in the presence of activating oncogenes represents an unexplored area in terms of cellular responses to pathway inhibitors and may open new approaches to modulating or predicting patient responses to drugs which target Ras/ERK signalling in cancer.