Researchers from Jonsson Comprehensive Cancer Center at UCLA have illuminated molecular “crosstalk” in pancreatic cancer cells, identifying vulnerabilities that could provide a target for therapeutic drugs already being studied in several cancers.
The study was published in Cell Reports. It was led by Caius Radu, a researcher at JCCC and professor in the Department of Molecular and Medical Pharmacology at UCLA, and Timothy Donahue, chief of the division of surgical oncology and professor of surgery at the David Geffen School of Medicine at UCLA.
The preclinical research, using tumor cells from patients and cell line-derived xenograft tumors, focused 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 the molecule and often become resistant to treatment with radiation, chemotherapy, and immune checkpoint blockade.
“We determined that a subset of PDAC tumors exhibit an intrinsic interferon response that has not been modeled by standard cell culture conditions,” Evan Abt, a postdoctoral researcher in Radu’s lab and co-first author of the article with Thuc Le, adjunct assistant professor in molecular and medical pharmacology, and Amanda Dann, a resident in surgery at the UCLA David Geffen School of Medicine, said in a statement. “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.”
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. To compensate, the cancer cells rely on the replication stress response signaling pathway, which can enable threatened DNA to survive, largely through the influence of ATR.
Donahue said one potential intervention deserving further exploration, according to the results of the study, is therapy that activates the STING signaling pathway.
“STING activation induces interferon signaling in PDAC cells and triggers ATR activation,” Donahue 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.”
