CRISPR Queries Anti-Cancer Drug Target
A team from Cold Spring Harbour Laboratory (CSHL) has published research that indicates the MELK gene is not good target for anti-cancer treatments, contrary to previously held beliefs. The study, which was published in eLife last week, is also thought to highlight inherent flaws in the scientific practices that were used to link the gene to cancer in the first place, potentially casting doubt on other, similar research.
“Our study is a good illustration of the self-correcting nature of science,” said CSHL Fellow and lead researcher Jason Sheltzer, PhD.
The Maternal Embryonic Leucine Zipper Kinase (MELK) gene has been linked to cancer for almost a decade, after it was discovered that the gene was overexpressed in many different cancer cell types. This led to several pharmaceutical companies investigating whether they could develop a cancer therapy that used MELK as a drug target, with some treatments reaching clinical trials.
For the last few years, however, the team at CSHL have been analysing the genomics of tumour tissue that has been surgically removed from cancer patients. The aim of their research has primarily been to identify which genes correlate with reduced patient survival rates by knocking on each gene at a time with CRISPR. As MELK had been shown to be essential for cancer cells in previous research, the team hoped to use the gene as a positive control mechanism.
“We thought we would eliminate MELK and show that it killed cancer cells. Then we could know that our CRISPR techniques were working,” Dr Sheltzer said. “But, to our great surprise, the cancer cells didn’t die. They just didn’t care”
Initially, the team believed that their observations may have been a result of a failure within their CRISPR technique. Further experiments were performed to investigate, revealing that this was not the case.
“We eventually had to conclude that our technique was fine,” said Dr Sheltzer. “Rather, it was the previous findings about MELK’s role in cancer that were incorrect.”
To account for this, the research team hypothesised that previously used techniques had made mistakes as a result of ‘off-target effects’. One commonly used technique is RNA interference, which exploits gene expression mechanisms to switch off target genes, and the team believe that use of this method led to secondary genes being knocked-out by accident, accounting for the cancer killing properties observed.
“You think you’re knocking down one gene, but in reality those techniques are not very specific, so you’re also hitting a number of other different genes,” said Dr Sheltzer. “We think that this might be a common problem. There are likely other genes like MELK out there and we’re going to use CRISPR to find them.”