How Pharmacological Treatments Avoid Pancreatic Cancer Cells


Most pancreatic cancer cells have mutations in the KRAS gene that allow for unregulated growth. In this image, the cancer-causing mutant version of the KRAS protein is stained red in pancreatic cancer cells. KRAS describes the plasma membrane: the outer layer of the cell. The cell nuclei are dyed blue. Researchers at the Cold Spring Harbor Laboratory discovered a new mechanism that could explain how pancreatic cancer cells develop resistance to drug treatments targeted at the KRAS protein. Credit: Derek Cheng / Tuveson Laboratory / CSHL

Cancer cells can become resistant to treatment through adaptation, making them notoriously difficult to defeat and highly lethal. Cold Spring Harbor Laboratory Cancer Center (CSHL) director David Tuveson and his team investigated the basis of the common “adaptive resistance” to pancreatic cancer. They discovered one of the backups these cells switch to when faced with drugs that kill cancer.

KRAS is a driving gene . Most pancreatic cancers have a mutation in the KRAS protein, causing uncontrolled growth. But drugs that shut down the mutant KRAS do not stop proliferation. He look for a way to avoid blocking and keep splitting. Derek Cheng, the study’s lead author and former student of the Training Program for Medical Scientists at Tuveson’s lab, compares this process to a ship’s reserve engines. He says, “You take yours , you are a bit on some backup engines. But it is achieved. The ship has not yet sunk. It still moves at a slower pace. In short, what we want to do is sink the ship. “

Tuveson and his team wanted to find out the “safety engines” in these cells. They used a technique called biotin proximity tagging to identify which other proteins interacted with the mutant KRAS. Cheng says, “I basically attach a spray can to my favorite protein, or rather the least preferred protein, in this case. So it fixes biotin, basically spraying biotin ‘paint’ to nearby proteins, and we can analyze it to find out which proteins were labeled “.

How Pharmacological Treatments Avoid Pancreatic Cancer Cells

When KRAS (red) is modified to remain in the cytoplasm or center of the cell, as seen in these cells in the pancreas, the protein does not promote cell division. In pancreatic cancer cells, a mutant form of KRAS stays close to the outer layer of the cell and interacts with nearby proteins to cause the cells to divide too much. Credit: Derek Cheng / Tuveson Laboratory / CSHL, 2021

Scientists found “biotin paint” in one called RSK1, which is part of a complex that holds a nearby group of proteins, called RAS proteins, latent. Scientists were shocked when they inactivated the KRAS mutant, the nearby RSK1 complex also stopped working. This allowed the RAS proteins to activate and take over the work of the missing mutant KRAS.

Parent cells may require drugs that can target several molecules simultaneously. Tuveson hopes to discover more of the players contributing to adaptation to cancer cells to improve future treatments.

The targeted drug is found to be effective in counteracting pancreatic tumors

More information:
Derek K. Cheng et al, Oncogenic KRAS has an RSK1 / NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073 / pnas.2016904118

Citation: How Drugs Avoid Pancreatic Cancer Cells (2021, June 22), Retrieved June 22, 2021 at dodge-drug.html

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