A new research paper has been published in Volume 17. onco target June 3, 2026, titled “The anticancer effect of PCAI in pancreatic cancer cells involves enhanced activation of MAPK and PI3K/AKT pathways.”
The study was led by first author Kweku Ofosu-Asante and corresponding author Nazarius S. Lamango of the Florida A&M University School of Pharmacy and Institute of Pharmaceutical Sciences at the Institute of Public Health in Tallahassee, Florida.
Pancreatic ductal adenocarcinoma is one of the most lethal cancers, primarily due to the high frequency of KRAS mutations that promote tumor growth and treatment resistance. Although targeted therapies for specific KRAS mutations have recently been developed, treatment options remain limited for many patients, highlighting the need for broader strategies that can target multiple cancers caused by KRAS.
In this study, the researchers investigated a class of experimental compounds known as polyisoprenylated cysteinylamide inhibitors (PCAIs) that were originally designed to interfere with aberrant KRAS signaling. Using pancreatic cancer cell lines with KRAS mutations, the researchers investigated how these compounds affect molecular pathways that regulate cancer cell survival, migration, invasion, and tumor growth.
Among the compounds tested, two PCAIs showed particularly potent anticancer activity. Further experiments focused on one lead compound, NSL-YHJ-2-27, which significantly reduced pancreatic cancer cell viability and strongly inhibited cell migration. At a concentration of just 1 μM, this compound blocked more than 90% of cancer cell migration, suggesting a potential role in limiting metastatic spread.
Researchers found that PCAI disrupts several cellular processes that cancer cells rely on for survival. Treatment reduced the levels of key monomeric G proteins involved in cell migration and invasion, altered the expression of genes associated with tumor progression, and induced major changes in the actin cytoskeleton, leading to cell rounding and loss of motility.
Unexpectedly, these compounds did not suppress these key KRAS downstream signaling pathways. Instead, it caused significant overactivation of both the MAPK and PI3K/AKT pathways. Although these pathways are typically associated with tumor growth, excessive activation can overwhelm cellular homeostasis and cause cell death. Consistent with this mechanism, PCAI-treated cells exhibited increased production of reactive oxygen species, activation of caspase enzymes, elevated levels of the proapoptotic protein BAX, and extensive apoptosis.
The research team also performed transcriptome analysis and identified significant changes in gene expression after treatment. Several genes with known tumor suppressor functions were upregulated, while genes associated with cancer progression and metastasis were reduced.
A three-dimensional tumor spheroid model provided further evidence of anticancer activity. PCAI treatment caused spheroid collapse, decreased infiltration into the surrounding matrix, and increased the proportion of apoptotic cells. This suggests that the compound maintains efficacy in a model that more closely resembles real tumors.
”One such promising class of drugs is PCAIs, which are designed to target oncogenic G proteins in a manner distinct from KRAS.G12C-Targeted drug. ”
According to the authors, this finding is particularly noteworthy because PCAI appears to be able to target cancer cells caused by multiple KRAS mutations rather than a single variant. This widespread activity may help overcome some of the limitations associated with currently available KRAS-targeted therapies.
Overall, this study demonstrates that PCAI exerts significant anticancer effects on pancreatic cancer cells through disruption of critical signaling networks, induction of oxidative stress, and activation of apoptosis. These findings support further investigation of PCAI as a potential therapeutic candidate for pancreatic cancer and other KRAS-induced malignancies.
sauce:
Reference magazines:
Ofosu Asante, K. others. (2026). The anticancer effects of PCAI in pancreatic cancer cells involve overactivation of MAPK and PI3K/AKT pathways. onco target. DOI: 10.18632/oncotarget.28879. https://www.oncotarget.com/article/28879/text/
