Researchers identify signaling mechanisms in pancreatic cancer cells
that could provide treatment targets

Date:
January 11, 2022
Source:
University of California - Los Angeles Health Sciences
Summary:
Scientists have provided new insights into molecular 'crosstalk'
in pancreas cancer cells, identifying vulnerabilities that could
provide a target for therapeutic drugs already being studied in
several cancers.



FULL STORY ========================================================================== Research led by scientists at the Jonsson Comprehensive Cancer Center
(JCCC) at UCLA provides new insights into molecular "crosstalk" in
pancreas cancer cells, identifying vulnerabilities that could provide
a target for therapeutic drugs already being studied in several
cancers. This interdisciplinary research was led by a team of JCCC investigators, Dr. Caius Radu, an expert in cancer cell metabolism,
and Dr. Timothy Donahue, a pancreas cancer surgeon and an expert in
pancreas cancer biology.


========================================================================== "Pancreatic ductal adenocarcinoma, which is highly resistant to current therapies, is expected to become the second most common cause of
cancer-related deaths in the United States within this decade," said
senior author Caius Radu, MD, a researcher at Jonsson Comprehensive
Cancer Center at UCLA and Professor in the Department of Molecular
and Medical Pharmacology at UCLA. "Results of this study increase our understanding of the inflammatory microenvironment within these tumors
and suggest targeted pharmacological strategies that could be employed to leverage this hallmark feature of pancreas cancer by current treatments."
The preclinical research, using tumor cells from patients and cell
line-derived xenograft tumors, was published online at Cell Reports
on Jan. 11. It centers on STING-driven type I interferon, an immune
system signaling molecule that impairs cancer cell proliferation in lab
studies but tends to have the opposite effect in clinical practice, where
tumor cells adapt to them and often become resistant to treatment with radiation, chemotherapy and immune checkpoint blockade. Interferons are produced in immune and other cells, including some types of cancer cells.

"We determined that a subset of PDAC tumors exhibit an intrinsic
interferon response that has not been modeled by standard cell culture conditions. Using several advanced techniques, we found that interferon signaling causes the tumor cells to rely on a specific signaling pathway
for survival. However, if we inhibit a protein called ATR, which plays
an important role in this signaling pathway, we can cause catastrophic
damage to the cancer cells' DNA and induce programmed cell death," said
Evan Abt, a postdoctoral researcher in Dr. Radu's lab and co-first author
of the article with Thuc Le, adjunct assistant professor in Molecular
and Medical Pharmacology, and Amanda Dann, MD, a resident in surgery at
the UCLA David Geffen School of Medicine.

Results suggest that new small molecule drugs that inhibit ATR and are
being studied for treatment of several cancers, including PDAC, could
be used in combination with interferon "amplification" to thwart the
tumor cells' ability to escape.

The researchers defined a series of molecular interactions leading to a
cascade of intracellular events. Through its influence on several genes, interferon alters the metabolic processes supporting the foundation of
the cancer cells' DNA, reducing the supply of biochemical building blocks needed for the DNA to survive. To compensate, the cancer cells rely on a signaling pathway - the replication stress response signaling pathway -
that can enable threatened DNA to survive, largely through the influence
of ATR.

Dr. Donahue said one potential intervention deserving further exploration, according to results of the study, therapy that activates another
signaling pathway, called STING.

"STING activation induces interferon signaling in PDAC cells and triggers
ATR activation," he said. "This strategy would enhance the attack brought
about through interferon signaling while preventing escape through
the collateral pathway by shutting it down with ATR-inhibiting drugs." ========================================================================== Story Source: Materials provided by University_of_California_-_Los_Angeles_Health_Sciences.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Evan R. Abt, Thuc M. Le, Amanda M. Dann, Joseph R. Capri, Soumya
Poddar,
Vincent Lok, Luyi Li, Keke Liang, Amanda L. Creech, Khalid Rashid,
Woosuk Kim, Nanping Wu, Jing Cui, Arthur Cho, Hailey Rose Lee,
Ethan W. Rosser, Jason M. Link, Johannes Czernin, Ting-Ting Wu,
Robert Damoiseaux, David W. Dawson, Timothy R. Donahue, Caius
G. Radu. Reprogramming of nucleotide metabolism by interferon
confers dependence on the replication stress response pathway in
pancreatic cancer cells. Cell Reports, 2022; 38 (2): 110236 DOI:
10.1016/j.celrep.2021.110236 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220111112032.htm

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