Most pancreatic tumors are caused by a mutation in the KRAS protein, a cell division-inducing gene that leads to uncontrolled growth. As medicines that inhibit mutant KRAS do not stop the proliferation, these cancer cells find a way around the obstruction and continue to divide.
It may be recalled that the founder of Apple Inc. and pioneer in the computers field, Steve Jobs was also diagnosed with a rare form of pancreatic cancer, which eventually led to his death in 2011.
"You take away your main engine, you're kind of on some backup engines. But it's getting by on those. The ship isn't sinking yet. It's still moving at a slower pace. Ultimately what we want to do is sink the ship," explains Derek Cheng, the lead author of the study.
David Tuveson, Director of the Cancer Center at Cold Spring Harbor Laboratory (CSHL), and his team wanted to discover the "backup engines" in these cancer cells. They used a method known as biotin proximity labeling to determine which other proteins interacted with mutant KRAS.
"I basically attach a spray can to my favorite protein, or rather least favorite protein, in this case. And so it attaches biotin, basically spraying biotin 'paint' to nearby proteins, and we're able to analyze it to figure out what proteins were labeled," said Cheng.
The researchers discovered "biotin paint" on a protein called RSK1. This protein is part of a complex that keeps a nearby set of proteins known as RAS proteins quiescent. The scientists were taken aback when they discovered that when they inactivated mutant KRAS, the neighboring RSK1 complex also ceased operating. This allowed the RAS proteins to activate and take up the work of the mutant KRAS that was lacking.
Stopping pancreatic cancer cells may necessitate the use of medications that can target many molecules at the same time. Tuveson intends to discover more of the players involved in cancer cell adaptability in order to improve future treatments.
