Researchers Uncover Potential Target for “Undruggable” Form of Liver Cancer

By Eva Kiesler,

Pictured: Scott Lowe

In taking a new approach to finding treatments for hepatocellular carcinoma, MSK scientists have uncovered a potential drug target for this highly aggressive cancer.

Increasingly, scientists are findings ways to shortcut the search for new cancer therapies. In a recent effort focused on hepatocellular carcinoma (HCC), a common and often aggressive form of liver cancer, a team of Memorial Sloan Kettering researchers discovered a way to thwart the cancer in mice, opening new possibilities for developing targeted drugs against it.

Rather than focusing only on genes known to drive this cancer — for which no effective drugs may exist — the researchers targeted other genes in tumor cells for which drugs are already available or being developed. The study was led by biologist Scott Lowe, Chair of the Cancer Biology and Genetics Program and the Geoffrey Beene Cancer Research Center, and reported in the journal Genes & Development in August.

No Obvious Drug Targets

According to some estimates, HCC is the third leading cause of cancer-related death worldwide, and its incidence is on the rise. In studying the genome of HCC tumors derived from patients, scientists at MSK and elsewhere have identified a number of gene changes that are responsible for driving the disease, including mutations in a gene called Myc.

But to their disappointment, none of these mutations are “druggable” — in other words, patients whose tumors carry these alterations can’t be offered a drug or a clinical trial that would potentially benefit them.

In many other cancers, such as lung cancer and melanoma, molecular characterization has led to the discovery of mutations that make tumor cells vulnerable to specific targeted therapies. “But HCC remains a disease for which no effective drugs exist,” Dr. Lowe says. “Even though we’ve learned about a number of things that are important in keeping these cancers alive, genomic studies haven’t led to any obvious ways to treat them.”

Back to top Arrow (up) icon.Icon pointing upwards. Usually means that the containing element can be opened and closed.

Searching by RNA Interference

Rather than looking for changes in the DNA sequence of HCC tumors, Dr. Lowe and his co-workers set out to try a different approach. His lab developed methods to shut down the activity of almost every gene in a cell one by one, to determine what the gene’s biological function is or whether the cell needs it to grow or survive. These methods, which are based on a technology called RNA interference (RNAi), also make it possible to screen cancer cells for potential drug targets.

“The problem with RNAi screens is they are very challenging and time consuming,” Dr. Lowe says, “and since HCC is a lethal cancer, we just can’t spend a decade looking for a drug.”

To speed the process, the researchers chose to confine the search to genes for which drugs already existed or were being developed. Following this approach, they identified a number of genes whose activity could be therapeutically stifled to kill HCC cells.

Back to top Arrow (up) icon.Icon pointing upwards. Usually means that the containing element can be opened and closed.

A Doorway to Treating Certain Tumors

The investigators found that targeting one of the genes, which codes for an enzyme called CDK9, might be particularly effective in a subset of patients whose tumors carry mutations in the Myc gene. “Our results demonstrate how CDK9 and Myc ‘talk’ to each other to drive tumor progression,” Dr. Lowe explains, “and that inhibiting CDK9 with a type of drug called a kinase inhibitor could be an effective way to control that progression.”

The CDK9-inhibitors that currently exist are not good enough to be tested in patients, however. “The compounds are not very specific and there’s a risk they could interfere with other proteins whose molecular structure is similar to that of CDK9,” he says. “This could lead to adverse side effects.”

Yet, he adds, these drug molecules do provide a starting point for chemists to develop new, more-precise compounds that potentially could be used to target HCC cells without damaging normal cells.

Back to top Arrow (up) icon.Icon pointing upwards. Usually means that the containing element can be opened and closed.

This research was supported in part by the National Institutes of Health under grant numbers CA008748, CA176671, CA16840902, and CA013106.


My 41 year old son was Dx with stage 111 colon cancer end of year 2015. He went thru 6 months of chemo. December 2016 he had colonoscopy ct scan and cea level. His cea level was less than 1. Went for his cea level check went up to 51. He is in Perth Australia. Went for his pet scan. Question is he has no symptoms at all . Knowing colon cancer can metastasis to liver and lung. What are his chances. I am the mother was also an oncology nurse. Desperately looking for answers

Dear Yvette, we're very sorry to hear about your son's diagnosis. Unfortunately we are not able to answer questions about prognosis on our blog. We recommend that you discuss your concerns with his healthcare team. Thank you for your comment, and best wishes to you and your family.

Add new comment

We welcome your questions and comments. While we share many of them with our world-class doctors and researchers, we regret that in order to protect your privacy, we are not able to make personal medical recommendations on this forum, nor do we publish comments that contain your personal information. If you would like to consult with an MSK doctor, we encourage you to make an appointment at 800-525-2225 or request an appointment online.

Your email address is kept private and will not be shown publicly.