Publish Date: 
Friday, July 25, 2014 - 12:45

By Fiona McMillan

Researchers at The University of Queensland Diamantina Institute have discovered that the answer may lie in the way melanoma cells deal with tangled DNA.

When any cell divides, a new, identical set of chromosomes must be made. The chromosomal DNA becomes entwined as a normal part of this replication process. But before the cell can split in two, the DNA must be properly detangled.

Recently Associate Professor Brian Gabrielli and his colleagues published their discovery that a cellular ‘checkpoint’ that identifies and fixes tangled (‘catenated’) DNA is defective in 67% of melanomas. Consequently, the melanoma cell attempts to divide while its chromosomes are still entwined. This increases genomic instability, which promotes cancer progression.
In their journal article published in Pigment Cell and Melanoma Research, the group reveal that they have now found evidence that the breakdown of this DNA detangling checkpoint facilitates treatment resistance by causing over-activation of an important cell survival pathway.

“We were looking for genes and pathways that compensate for the loss of this important stress response mechanism,” explains Gabrielli. “We identified the PI3K pathway as being over activated as a compensatory response.”
Many chemotherapy agents work by causing DNA damage, which triggers the self-destruction mechanism in rapidly dividing cells, including cancer cells. In some cancers, the PI3K pathway overrides this self-destruct switch.
This is the first time a possible trigger for the over-activation of the PI3K pathway has been observed in melanoma. Moreover, Gabrielli and his fellow researchers found that cells with the defective DNA detangling checkpoint were three times more sensitive to small molecule inhibitors of PI3K. They had become dependent on the pathway for survival. 
The PI3K pathway has been the focus of drug development efforts for some time, showing promise in some cancers but not others. The pathway has proved a challenging target due to its complexity, but advances are being made and a number of clinical trials are underway.
Gabrielli does not believe PI3K inhibitors would function effectively as a solitary treatment for melanoma, but he thinks they could have benefit in combination with existing drugs.
 “A predication from our work is that PI3K inhibitors may sensitise melanomas with the checkpoint defect to standard chemotherapy, which does not normally work effectively in melanoma. We should test this in preclinical models.” 
This work broadens our understanding of how skin cells regulate genomic stability, and how this stability is lost as melanoma develops. Gabrielli wants to investigate precisely how the checkpoint defect over-activates the PI3K pathway, which could lead to the identification of new therapeutic targets.

MEDIA: Kate Templeman on 0409 916 801 or [email protected]

Melanoma cell dividing B0003294 Credit

Paul J. Smith & Rachel Errington,
Wellcome Images

Molecular structure of PI3K
Phosphoinositide 3-kinases