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“Taken together, these data obtained using pancreatic cancer cells with KRAS mutations suggest the ability of the PCAIs to prevent metastasis and tumor growth, strongly indicating their potential to serve as effective targeted therapies for treating cancer types driven by the multiple mutant forms of KRAS.”

BUFFALO, NY – June 8, 2026 – A new research paper was published in Volume 17 of Oncotarget on June 3, 2026, titled “The anticancer effects of PCAIs in pancreatic cancer cells involve MAPK and PI3K/AKT pathways hyperactivation.”

The study was led by first author Kweku Ofosu-Asante and corresponding author Nazarius S. Lamango from the Florida A&M University College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health in Tallahassee, Florida.

Pancreatic ductal adenocarcinoma is among the deadliest forms of cancer, due in large part to the high frequency of KRAS mutations that drive tumor growth and resistance to treatment. Although targeted therapies have recently been developed for specific KRAS mutations, many patients continue to have limited treatment options, highlighting the need for broader strategies capable of targeting multiple KRAS-driven cancers.

In this study, researchers investigated a class of experimental compounds known as polyisoprenylated cysteinyl amide inhibitors (PCAIs), which were originally designed to disrupt abnormal KRAS signaling. Using pancreatic cancer cell lines carrying KRAS mutations, the team explored how these compounds affect cancer cell survival, migration, invasion, and the molecular pathways that regulate tumor growth.

Among the compounds tested, two PCAIs demonstrated particularly strong 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, the compound blocked more than 90% of cancer cell migration, suggesting a potential role in limiting metastatic spread.

The researchers found that PCAIs disrupted several cellular processes that cancer cells rely on for survival. Treatment reduced levels of key monomeric G-proteins involved in cell movement and invasion, altered the expression of genes associated with tumor progression, and caused major changes in the actin cytoskeleton, leading to cell rounding and loss of mobility.

Unexpectedly, the compounds did not suppress these major KRAS downstream signaling pathways. Instead, they caused pronounced hyperactivation of both the MAPK and PI3K/AKT pathways. While these pathways are typically associated with tumor growth, excessive activation can overwhelm cellular homeostasis and trigger cell death. Consistent with this mechanism, PCAI-treated cells showed increased production of reactive oxygen species, activation of caspase enzymes, elevated levels of the pro-apoptotic protein BAX, and widespread apoptosis.

The team also performed transcriptomic analyses and identified substantial changes in gene expression following treatment. Several genes with known tumor-suppressive functions were upregulated, while genes associated with cancer progression and metastasis were reduced.

Three-dimensional tumor spheroid models provided additional evidence of anticancer activity. PCAI treatment caused spheroid disintegration, reduced invasion into surrounding matrices, and increased the proportion of apoptotic cells, suggesting that the compounds remain effective in models that more closely resemble real tumors.

“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 KRAS^G12C-targeting drugs.”

According to the authors, the findings are particularly noteworthy because PCAIs appear capable of targeting cancer cells driven by multiple KRAS mutations rather than a single mutant form. This broader activity could potentially help overcome some of the limitations associated with currently available KRAS-targeted therapies.

Overall, the study demonstrates that PCAIs exert significant anticancer effects in pancreatic cancer cells through disruption of critical signaling networks, induction of oxidative stress, and activation of apoptosis. These findings support further investigation of PCAIs as potential therapeutic candidates for pancreatic cancer and other KRAS-driven malignancies.

DOI: https://doi.org/10.18632/oncotarget.28879        

Correspondence to: Nazarius S. Lamango – [email protected]   

Keywords: cancer, PCAIs, PDAC, MAPK, PI3K/AKT, KRAS

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