Updates

We are excited to share the story behind our recent work, published in a scientific journal in 2024, where we uncovered a surprising vulnerability in some of the most aggressive cancers. Our work was one of two studies selected for the Biocity Turku Elias Tillandz prize this year.

Mutations in the RAS gene family—especially KRAS—are among the most common drivers of human cancers. For decades, scientists have tried to develop effective KRAS-targeted therapies, but progress has been slow and often frustrating.

In our study, we discovered that SHANK3, a protein best known for its role in neurons, also plays an important part in controlling KRAS growth signals inside cells. When SHANK3 is present, it binds to mutant KRAS in cancer cells and acts like a “brake”, keeping KRAS activity at a level that allows the cells to survive and grow. But when SHANK3 is removed, KRAS activity goes into overdrive. Instead of fueling tumour growth, this overload of signals becomes toxic, causing the cancer cells to die. This unexpected “Achilles’ heel” opens up a completely new way of tackling KRAS-driven cancers.

Taking this idea further, we developed anti-SHANK3 nanobodies—tiny antibody fragments—that specifically block the interaction between SHANK3 and KRAS. These nanobodies acted in the same way as removing SHANK3, pushing KRAS into self-destructive overactivation and killing the cancer cells.

Years ago, when we first started this work, the idea of pushing growth signals into overdrive instead of shutting them down as a cancer therapy was not well known, and it took a lot of time and effort to get our results out. Now, more and more studies show that hyper-activation could be a powerful new way to kill cancer cells.

In 2021, the FDA approved sotorasib, the first KRAS inhibitor, for patients with KRAS-mutated metastatic lung cancer. Sotorasib works by trapping KRAS in an inactive state, but it only targets one specific KRAS mutation. By contrast, our discovery could work across many different KRAS mutations, not just a single subtype, and opens the door to therapies for a wide range of KRAS-driven cancers.

You can read the full text of our work here: https://www.nature.com/articles/s41467-024-52326-1

Writer of the article is Hellyeh Hamidi, Research Coordinator from Johanna Ivaska’s research group.