A research team from the Florida A&M University College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health in Tallahassee, Florida, published findings on June 3 that identify a new class of compounds with potential therapeutic effects against KRAS-driven pancreatic cancer.
The study, led by first author Kweku Ofosu-Asante and corresponding author Nazarius S. Lamango, investigated polyisoprenylated cysteinyl amide inhibitors (PCAIs) for their ability to disrupt abnormal KRAS signaling in pancreatic ductal adenocarcinoma cells. Pancreatic ductal adenocarcinoma is one of the deadliest cancers due to frequent KRAS mutations that drive tumor growth and resistance to current treatments.
Using cell lines carrying KRAS mutations, researchers found that two PCAI compounds showed strong anticancer activity. One lead compound, NSL-YHJ-2-27, significantly reduced cancer cell viability and inhibited migration at low concentrations. At 1 µM concentration, it blocked over 90% of cancer cell migration. The treatment also disrupted key cellular processes including levels of monomeric G-proteins involved in movement and invasion, gene expression linked to tumor progression, and caused changes in the actin cytoskeleton resulting in loss of mobility.
Unexpectedly, rather than suppressing major downstream pathways associated with KRAS such as MAPK and PI3K/AKT, PCAIs induced hyperactivation of these pathways. This excessive activation appeared to overwhelm cellular homeostasis and trigger apoptosis. Treated cells exhibited increased reactive oxygen species production, caspase enzyme activation, higher levels of pro-apoptotic protein BAX, and widespread apoptosis.
Transcriptomic analyses revealed substantial gene expression changes after treatment: genes with tumor-suppressive functions were upregulated while those associated with progression were reduced. In three-dimensional tumor spheroid models designed to mimic real tumors more closely than traditional cell cultures, PCAI treatment led to spheroid disintegration and reduced invasion into surrounding matrices.
"One class of such promising agents is the PCAIs that were designed to target oncogenic G-proteins in a manner that is different from the KRASG12C-targeting drugs," said the authors. They added that these findings are notable because PCAIs appear capable of targeting multiple forms of mutant KRAS rather than only a single variant—a limitation seen with some existing therapies.
