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How pancreatic cancer cells dodge drug treatments

Date:
June 22, 2021
Source:
Cold Spring Harbor Laboratory
Summary:
Pancreatic cancer cells typically rely on a mutant version of the KRAS protein to proliferate. These cancer cells can also survive losing KRAS by activating alternative growth pathways. Scientists discovered a new interaction between mutant KRAS and a protein complex called RSK1/NF1 that may be the source of this adaptive resistance.
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FULL STORY

Cancer cells can become resistant to treatments through adaptation, making them notoriously tricky to defeat and highly lethal. Cold Spring Harbor Laboratory (CSHL) Cancer Center Director David Tuveson and his team investigated the basis of "adaptive resistance" common to pancreatic cancer. They discovered one of the backups to which these cells switch when confronted with cancer-killing drugs.

KRAS is a gene that drives cell division. Most pancreatic cancers have a mutation in the KRAS protein, causing uncontrolled growth. But, drugs that shut off mutant KRAS do not stop the proliferation. The cancer cells find a way to bypass the blockage and keep on dividing. Derek Cheng, the lead author of the study and a former Medical Scientist Training Program student in the Tuveson lab, compares this process to backup engines on a ship. He says:

"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."

Tuveson and his team wanted to figure out the "backup engines" in these cancer cells. They used a technique called biotin proximity labeling to identify what other proteins interacted with mutant KRAS. Cheng says, "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."

The scientists found "biotin paint" on a protein named RSK1, which is part of a complex that keeps a nearby group of proteins, called RAS proteins, dormant. The scientists were surprised to discover that when they inactivated mutant KRAS, the nearby RSK1 complex stopped working as well. This allowed the RAS proteins to activate and take over the work of the missing mutant KRAS.

Stopping pancreatic cancer cells may require drugs that can simultaneously target multiple molecules. Tuveson hopes to uncover more of the players contributing to adaptation in cancer cells to improve future treatments.


Story Source:

Materials provided by Cold Spring Harbor Laboratory. Original written by Luis Sandoval. Note: Content may be edited for style and length.


Journal Reference:

  1. Derek K. Cheng, Tobiloba E. Oni, Jennifer S. Thalappillil, Youngkyu Park, Hsiu-Chi Ting, Brinda Alagesan, Nadia V. Prasad, Kenneth Addison, Keith D. Rivera, Darryl J. Pappin, Linda Van Aelst, David A. Tuveson. Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer. Proceedings of the National Academy of Sciences, 2021; 118 (21): e2016904118 DOI: 10.1073/pnas.2016904118

Cite This Page:

Cold Spring Harbor Laboratory. "How pancreatic cancer cells dodge drug treatments." ScienceDaily. ScienceDaily, 22 June 2021. <www.sciencedaily.com/releases/2021/06/210622132306.htm>.
Cold Spring Harbor Laboratory. (2021, June 22). How pancreatic cancer cells dodge drug treatments. ScienceDaily. Retrieved December 4, 2024 from www.sciencedaily.com/releases/2021/06/210622132306.htm
Cold Spring Harbor Laboratory. "How pancreatic cancer cells dodge drug treatments." ScienceDaily. www.sciencedaily.com/releases/2021/06/210622132306.htm (accessed December 4, 2024).

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