Potential progress in the fight against RAS-related cancers

Each year, more than 3 million people are diagnosed with cancer caused by mutations in three genes of the RAS family: KRAS, NRASAND HRAS. Mutations in the RAS family are associated with many types of cancer.

KRAS mutations occur in pancreatic cancer, colon cancer, lung cancer and some types of ovarian cancer. NRAS mutations are frequently observed in melanoma, acute myeloid leukemia, and thyroid cancer. HRAS mutations are commonly found in bladder cancer, head and neck cancer, and some types of skin cancer.

Now, the MSK research team has identified a therapeutic approach that has shown promise in mouse models. In a new study, scientists in Dr. Piro Lito’s lab showed that some inhibitors can short-circuit uncontrolled signaling caused by mutations that drive cancer development. The results of their research were published on October 30, 2024 in Natureone of the leading scientific journals in the world.

We spoke with Dr. Lito about the study’s results and implications.

For non-scientists, can you explain what this research showed?

Mutations – i.e. errors in the DNA code – cause these key proteins from the RAS family to remain constantly active and send a constant stream of signals that promote uncontrolled cell division and growth, leading to the development and progression of various cancers.

Scientists have long worked to find drugs capable of interrupting this constant signaling, but have been unsuccessful.

Now my lab, through efforts led by lab members Dr. Antonio Cuevas-Navarro and Dr. Yasin Pourfarjam, has identified an approach that has proven effective in restoring normal function of these mutant proteins in mouse models of cancer.

What is the significance of this discovery?

We found that these compounds, called three-complex inhibitors, stimulate a process known as GTP hydrolysis, which results in the deactivation of problematic downstream signaling and tumor growth. This is something scientists have been trying for decades, to no avail.

We therefore believe that this research could lay the groundwork for the development of a new class of drugs that, if successful, could improve the care of the millions of people whose cancers are caused by these mutations.

What are the next steps?

While we are excited and optimistic, it is important to say that this research is still in quite early stages.

The process of developing and optimizing small molecule drugs for human use takes years, and there are many reasons why even the most promising compounds do not make it through the full drug development process and receive approval from the U.S. Food and Drug Administration.

It is also worth noting that the effect was stronger for some types of mutant RAS proteins than for others.

Nevertheless, our research continues and our goal is to move to early stage clinical trials as quickly as possible.