Undruggable Cancer Targets: Tackling Difficult Drug Design
Hundreds of different types of cancer occur in humans, but they all have one thing in common. Every cancer cell contains alterations that lead to the production of abnormal proteins responsible for uncontrolled cell growth and survival. Many precision cancer medicines block the activity of these abnormal proteins by binding to them. However, there are cancer-driving proteins that have eluded all attempts to stop their harmful effects. For years, researchers have struggled to develop treatments that work on these so-called “undruggable” targets. Frequently, the pharmaceutical industry has considered them too risky to explore, but NCI has long supported this research.
Over the past 5 to 10 years, NCI-funded researchers have developed new strategies to tackle these difficult targets thanks to advances in chemistry, computational approaches, and imaging coupled with a deeper understanding of cancer biology. For example, in 2021, the Food and Drug Administration (FDA) approved the first drug targeting a mutated form of a protein called KRAS. Finding a drug to target KRAS, one of the most frequently mutated drivers in cancer, is a celebrated milestone that provides new proof of principle for future drug development.
Armed with novel tools and more knowledge about cancer biology than ever before, researchers have made significant progress developing ways to target previously undruggable cancer drivers. NCI support has contributed to research on degrading cancer-driving proteins (an alternative to blocking their activity), manipulating interactions between interdependent proteins, and targeting nonprotein cancer-driving molecules. However, a substantial number of important proteins have yet to be targeted successfully, and a full understanding of all potential therapeutic targets in cancer remains elusive.
Sustained investment is needed to seize on the progress that has been made so far—from foundational discoveries to new tools and technologies. Spurred by recent advances in drug design, we are approaching a point where very few cancer drivers may be considered “undruggable.” Getting to that point could result in strategies to target almost any abnormal protein and medicines for more patients.
Leveraging basic research for successful drug design
NCI has a long history of supporting discovery science—the type of fundamental research that leads to novel approaches to cancer treatment. One shining example of this is support that ultimately led to the development of sotorasib (Lumakras), an FDA-approved drug for non-small cell lung cancer. The success of sotorasib is grounded in years of NCI-funded basic research in structural biology and chemistry.
Sotorasib is a small molecule that irreversibly binds to KRAS proteins, which are one of the most prevalent drivers of non-small cell lung cancers and can cause unrestrained cell growth when mutated. After a series of breakthrough studies on KRAS protein structure, supported in part by the NCI-funded RAS Initiative, researchers keyed in on the unique ability of sotorasib to lock KRAS in its inactive form when it harbors a specific alteration. A subsequent clinical trial showed that sotorasib controlled non-small cell lung cancer in about 80% of patients with the relevant KRAS mutation.
This exciting work serves as a launchpad for new ways to target proteins that develop resistance to available targeted therapies. For example, cancers treated with drugs that target abnormal EGFR proteins, another prevalent cancer driver, are prone to developing drug resistance. While the EGFR-targeting drugs initially treat the cancer, in many cases the drugs ultimately lose their effectiveness as resistant forms of abnormal EGFR arise, rendering EGFR undruggable in the patient. NCI-supported researchers have found preliminary success by locking abnormal forms of the EGFR protein into an inactive shape, like researchers did for KRAS.
NCI sustains the sort of infrastructure that powers this type of success. For example, researchers need access to cutting-edge microscopy to generate high-quality protein structures, and they need data to be made publicly available for others to use. Federal programs bolster access to these resources for the scientific community, including for researchers and institutions that lack their own infrastructure for this critical work.
Discovering RNA as a drug target and a potential drug
Supported by growing genomic databases and the advent of fast, inexpensive genetic engineering technology, NCI-supported researchers are broadening their scope beyond proteins and into RNA-based drug design. Our knowledge of the various types of RNA continues to expand. One type of RNA is an intermediary molecule that helps convert DNA instructions into proteins, a tempting target to prevent the effects of harmful gene alterations. Other types of RNA regulate basic functions in the cell.
New RNA-targeting drug strategies deepen the pool of druggable targets in cancer cells. In one study, NCI researchers discovered a natural product that binds cancer-driving microRNAs, a specific type of RNA product, and stops colon cancer cells from multiplying in a petri dish. This preliminary study sets the stage to investigate RNA-targeting drugs further, but more research is needed to understand all RNA alterations and druggable features in cancer cells.
Some researchers are using RNA as the drug itself. NCI-supported scientists from the Fred Hutchinson Cancer Research Center and Memorial Sloan Kettering Cancer Center created a synthetic RNA that makes cancer cells vulnerable to the drug ganciclovir (Zirgan). Their approach worked in mice implanted with leukemia, uveal melanoma, and breast cancer cells that shared a specific RNA-processing mutation. With more synthetic RNA research, we can imagine treatment options that could multiply the number of cancer drugs available to patients.
Driving innovative cancer drug design with cutting-edge technologies
Federal support is vital to new drug development—whether those drugs target proteins, RNA, or other cell components—since industry is reluctant to pursue this type of foundational research until proof of principle is established. Several exciting developments are playing out in NCI-supported laboratories around the country.
For example, researchers are exploring nanomaterials that can detect cancer byproducts in body fluids, visualize cancer cells in the body, and deliver drugs directly to the cancer cells. In one study, NCI-supported researchers at the Washington University School of Medicine in St. Louis treated aggressive metastatic breast cancer in mice using nanotechnology to activate drugs at the site of cancer cells only, reducing toxic side effects on healthy cells.
Other NCI-supported researchers are finding new and better ways to link molecules together to design more effective cancer drugs. This includes linking drugs to cancer-seeking antibodies or creating bifunctional molecules that can both find and destroy cancer-driving proteins. Bolstering these technological advancements could lead to an entirely new class of highly targeted cancer treatments and shrink the list of undruggable proteins.
One cutting-edge approach that has received notable attention from both academic researchers and the pharmaceutical industry is proteolysis targeting chimeras (PROTACs), which are bifunctional molecules that bind cancer-driving proteins and target them for destruction. Early efforts have culminated in the development of the first clinical agents of this class targeting solid tumors. This technology has also inspired a tidal wave of interest in the development of small molecule degraders using this approach, as well as “molecular glues” that hold together two proteins that wouldn’t normally interact.
More recently, NCI-supported researchers have successfully used PROTAC technology to suppress tumor growth in animals by targeting the otherwise hard-to-block EZH2 protein, which has been linked to cancer progression and poor survival. These early results suggest PROTACs offer great promise. However, developing effective PROTAC molecules is challenging, and more federal support is needed to further refine this cutting-edge technology.
Now imagine taking decades of information about cancer biology and drug design and using computers to predict the most efficient cancer drugs. Computational biology researchers are doing just that. Continued federal support for computer-based drug design is critical to develop and maintain the type of computational power and data sets needed for drug design analysis. Investments in computational capability have the potential to impact all areas of drug design and lead to novel pharmaceutical approaches that could make a major impact on ending cancer as we know it.