Scientists Find the Chink in the Armor of a Deadly Childhood Cancer Protein

Highlights:

• Neuroblastoma research advances as scientists uncover the mechanisms of cancer-driving proteins, offering new insights for oncology treatments.
• A once-incurable childhood cancer is now within reach of a cure, thanks to cutting-edge research breakthroughs.

For decades, a single protein has been shielding one of childhood’s deadliest cancers from every drug thrown at it and scientists have finally found where to hit back. Key trade routes and energy markets are in turmoil, accelerating healthcare cost pressures, affecting both developed and emerging economies.

Researchers at Sweden’s Linkoping University, in collaboration with the University of Toronto, have mapped an exact interaction point between two cancer-driving proteins in neuroblastoma, which is a rare but aggressive tumour of the nervous system that afflicts children, most often before age two. The findings, published in Nature Communications, mark a watershed moment in oncology, with significant lessons for cancer researchers.

N-MYC, with the “N” standing for neuroblastoma, the cancer in which the protein was first identified, is directly linked to poorer prognosis. About half of children affected by N-MYC carry high-risk tumours with a significantly lesser chance of cure. What makes N-MYC so dangerous and yet so stubbornly resistant to treatment, comes down to the outrageous biology linked to it:

• Unlike most proteins, which hold a fixed three-dimensional shape that drugs can easily latch onto, N-MYC is structurally disordered as it constantly shifts and changes.
• MYC proteins are involved in the growth and division of healthy cells, too, meaning any drug must be surgically accurate, targeting only the cancerous interaction, not the broader cellular function.
• N-MYC has long been considered directly “undruggable” therapeutically, leaving clinicians with few targeted options.

“Classic medical drug development is based on the fact that there is a pocket on the protein that you block with a molecule that binds there, much like Lego bricks that fit together,” explains Maria Sunnerhagen, professor of structural biology at Linköping University. “But MYC keeps changing shape.”

That shapeshifting quality is precisely what the new research set out to exploit. It does this by dismantling its partnership with Aurora A, a kinase protein that functions as its protector, rather than targeting the N-MYC itself. In MYCN-amplified neuroblastoma cells, N-MYC’s stability is increased through binding with Aurora kinase A, which prevents its natural degradation. Essentially, it keeps a lethal protein alive far longer than it should be.

Using nuclear magnetic resonance (NMR) spectroscopy, AI-driven calculations and molecular analyses, the team pinpointed the exact region where N-MYC and Aurora A anchor to each other. As one would reckon, this is a discovery that transforms an abstract therapeutic hypothesis into something mappable and therefore targetable. Moreover, the researchers also identified a small molecule capable of physically breaking the two proteins apart, laying early groundwork for future drug development.

“To stop an interaction, you need to know where it’s happening. Even though N-MYC constantly changes shape, we now know where the two proteins anchor to each other. This provided clues as to what the medication should look like,” said Johanna Hultman, PhD student on the research team.

The implicit promise running beneath the science is that the “undruggable” label has always been a function of incomplete knowledge, not impossibility. With the binding site now fully mapped and a disruptive molecule in hand, the path forward leads to pharmacologists and clinical cell biologists who can convert structural insight into therapeutic reality.

“Today, we can cure many cases of childhood cancer that were incurable ten years ago. But there’s still an important group of childhood tumours that evade cure,” Sunnerhagen noted. This research may be the key to finally making a turnaround in this regard.