Poster Presentation 38th Lorne Cancer Conference 2026

DUSP4 copy loss: an alternate mediator of ERK/MAPK signaling activation and a novel driver of colorectal cancer (#226)

Kristen A Needham 1 2 , Fiona Chionh 1 2 3 , Stan Kaczmarczyk 1 , Dmitri Mouradov 4 , Camilla M Reehorst 1 , Laura J Jenkins 1 2 , Ian Y Luk 1 2 , Conor Kearney 1 , Rebecca Nightingale 1 , Jack P Collin 1 2 , Oliver Sieber 4 , John M Mariadason 1 2
  1. Olivia Newton-John Cancer Research Institute, Heidelberg, VICTORIA, Australia
  2. School of Cancer Medicine, La Trobe University, Melbourne, Vic, Australia
  3. Austin Hospital, Heidelberg, Melbourne, Victoria, Australia
  4. Walter and Eliza Hall Institute, Melbourne, Vic, Australia

Over 15,000 Australians are diagnosed with colorectal cancer (CRC) annually. Despite available treatments, the 5-year survival rate for metastatic CRC is <14%. 

 

Hyper-activation of the ERK/MAPK-pathway is a key driver of CRC.  Genetic alterations of ERK/MAPK-pathway components (RAS, BRAF, EGFR, HER2) that drive constitutive pathway activation occur in ~60% of CRC’s, for which targeted therapies are now clinically utilised.  While the remaining ~40% of CRC’s lack genetic alterations in known ERK/MAPK activators, a significant proportion still likely depend on this pathway for growth. The mechanisms driving ERK/MAPK-pathway activation in these wild-type CRC’s remain unclear, and uncovering novel drivers could enable development of new targeted therapies.

 

As the primary effector of the ERK/MAPK-pathway, ERK is regulated by the map-kinase phosphatase (MKP) subset of dual-specificity phosphatases (DUSP), and the role of their deletion in CRC remains unclear. We examined the deletion frequency of MKP’s in the TCGA cohort of 231 microsatellite-stable CRC’s, and identified DUSP4 as the most frequently deleted.  We therefore hypothesised that DUSP4 copy loss may be an alternate mediator of ERK/MAPK activation, and an unknown driver of CRC. 

 

To investigate this, we examined the frequency of DUSP4 deletion and the relationship with genomic alterations in other components of the ERK/MAPK-pathway (TCGA dataset) in CRCs. We found that DUSP4 copy loss occurs in ~48% of CRCs, and is significantly enriched in tumours lacking BRAF/RAS mutations (P<0.05). 

 

Next, to determine the functional significance of DUSP4 loss in this context, we re-expressed DUSP4 in BRAF/RAS wild-type CRC cell lines with genetic deletion of DUSP4 and lacking endogenous expression. DUSP4 re-expression suppressed ERK/MAPK-pathway output, both basally and upon EGF-stimulation, consistent with its role as a critical negative regulator of ERK output.  DUSP4 re-expression also significantly reduced proliferation and colony formation in BRAF/RAS WT CRC cells. Finally, consistent with its tumour suppressive effect, DUSP4 re-expressing cells were selected against during cell line expansion.   

 

Our preliminary results support genomic DUSP4 loss as a facilitator of ERK/MAPK-pathway activation and proliferation in CRC. Validation of these findings in a mouse model is underway to determine the impact of Dusp4 deletion on colon homeostasis and Apc-driven colon tumorigenesis.

  1. Cornish, A.J., Gruber, A.J., Kinnersley, B., Chubb, D., Frangou, A., Caravagna, G., Noyvert, B., Lakatos, E., Wood, H.M., Thorn, S. and Culliford, R., 2024. The genomic landscape of 2,023 colorectal cancers. Nature, 633(8028), pp.127-136.
  2. Cancer Genome Atlas Network, 2012. Comprehensive molecular characterization of human colon and rectal cancer. Nature, 487(7407), p.330.
  3. Canceraustralia.gov.au