Undruggable Cancer Genes May Not Be Invincible
Nearly a third of all cancers have mutations in the gene KRAS, yet there are no drugs to combat these changes. And KRAS is not unusual—other common cancer genes are also considered "undruggable."
But as two new studies report, cancer cells driven by these genes may be vulnerable to another kind of attack. A technology called RNA interference can identify "normal" genes in tumor cells that are required for the survival of these cells, and one of these genes may turn out to be an Achilles' heel.
Two independent groups led by researchers at Harvard Medical School used this strategy to search for potential vulnerabilities in cancer cells with KRAS mutations. Both groups found proteins that were essential for the viability of the cells, including some protein kinases. These are promising targets because they can be inhibited by drugs. Imatinib (Gleevec) is one example.
As reported in the May 29 Cell, the researchers used short bits of RNA to target and silence individual genes in cells. While clinical trials will be needed to learn whether patients benefit from this approach, the findings are supported by smaller studies, including one that revealed potential drug targets for diffuse large B-cell lymphoma.
"What these screens do is give us potential leads for new cancer drugs," said Dr. Stephen Elledge, one of the lead investigators. "There must be whole networks of non-oncogenes out there that tumors depend on," he noted, but the genes are difficult to find because they do not have any mutations or alterations.
His team identified a number of genes related to mitosis, including one called PLK1, that are potential therapeutic targets. In tumor cells, KRAS mutations altered the fidelity of mitosis in a way that made the cells die when these genes were inhibited. Thus, cells with KRAS mutations may be vulnerable to antimitotic drugs that target these genes, the researchers said.
Cancer Cells Are "Rewired"
Their findings support the view that cells with cancer-causing mutations are genetically rewired and, through this process, acquire new dependencies. The pathways for growth and survival, for instance, are extensively rewired in cancer cells, and many non-oncogenes play critical roles in the operation of these pathways.
A gene not linked to cancer, STK33, was the top candidate of the second study, led by Drs. William Hahn and Gary Gilliland. Because the gene is essential for the viability of mutant KRAS-dependent cells, the researchers proposed that inhibiting the STK33 protein could potentially treat a broad spectrum of tumors associated with mutant KRAS genes.
In an accompanying commentary, Dr. Charles Sawyers of Memorial Sloan-Kettering Cancer Center said there were "important and immediate" implications for translating these results into the clinic. Identifying inhibitors of STK33 and PLK1 should be relatively straightforward, and clinical trials of such inhibitors could, in principle, begin in 1 to 2 years, noted Dr. Sawyers, who has led the development of targeted cancer drugs.
For now, the importance of these studies is to show that "RNA-interference technology offers a way to develop inhibitors of oncogenes that have until now been undruggable," he wrote in an e-mail. "KRAS mutations are very common, so finding an inhibitor has been a longtime goal of the field."
The Technology Has Arrived
In 1997, researchers at Fred Hutchinson Cancer Research Center predicted that cancer cells had genetic dependencies that could be exploited in drug development, but the tools for discovering these relationships have become available only recently. The reports by Drs. Elledge, Hahn, and Gilliland are among the first to show how researchers can observe, on a genome-wide scale, what happens when a single gene "goes missing" from a tumor cell.
Whether RNA-interference screens will become more common may depend in part on costs. Dr. Gilliland's group used technologies that are beyond the reach of most academic researchers, but the tools used by the other group are available and affordable, Dr. Sawyers noted.
"We need more people doing these genetic screens," said Dr. Elledge. "Hopefully, we have set the stage for this by giving people the information and tools they need to go out and ask these questions."
Given the complexity of cancer and the tendency of tumors to become resistant to single agents, more targets are certainly needed to treat people with this disease. Genetic screens may be part of the solution.
"The key point is that there are lots of potential vulnerabilities in cancer cells, and the technology has now arrived to discover them," he said.
—Edward R. Winstead