Abstract B065: Bioactive Compounds Derived from Alcea rosea Suppress KRAS-Driven Signaling and Cancer Stem Cell Plasticity in Pancreatic Ductal Adenocarcinoma

Background:

Activating KRAS mutations occur in more than 90% of pancreatic ductal adenocarcinoma (PDAC) cases and are major drivers of tumor progression, therapeutic resistance, and poor clinical outcomes. Persistent activation of the RAF/MEK/ERK signaling cascade promotes cancer stem cell (CSC) maintenance and tumor plasticity, limiting the efficacy of current targeted therapies. This study evaluated the therapeutic potential of bioactive compounds isolated from Alcea rosea to target KRAS-driven signaling and CSC-associated phenotypes in PDAC.

Methods:

Bioactive compounds isolated from the ethyl acetate extract of Alcea rosea were evaluated in KRAS-mutant human PDAC cell lines. Cytotoxicity was assessed by MTT assay, while colony formation, wound healing, and 3D spheroid assays evaluated tumorigenicity and stemness. Apoptosis was analyzed by DAPI/PI and AO/EtBr staining, ROS generation, mitochondrial membrane potential, and flow cytometry. Western blotting assessed p-MEK, p-ERK, Caspase-3, and PARP expression. Molecular docking against KRAS, MEK1, and ERK2 evaluated binding affinities, followed by 100 ns molecular dynamics simulations to assess complex stability, conformational dynamics, RMSD, RMSF, and hydrogen-bonding interactions.

Results:

Alcea rosea-derived compounds significantly reduced PDAC cell viability, clonogenic growth, migration, and 3D spheroid formation, indicating impaired cancer stem cell (CSC) self-renewal. Treatment increased ROS generation, disrupted mitochondrial membrane potential, and induced apoptosis, as evidenced by Caspase-3 activation and PARP cleavage. Western blot analysis demonstrated 1.3-fold and 2.2-fold reductions in MEK and ERK phosphorylation, respectively. Molecular docking revealed favourable binding of the bioactive compounds to KRAS, MEK1, and ERK2, while 100 ns molecular dynamics simulations confirmed stable ligand–protein complexes through consistent RMSD, RMSF, and hydrogen-bonding profiles.

Conclusions:

Alcea rosea-derived bioactive compounds exhibit potent anti-tumor activity against KRAS-mutant PDAC by inhibiting KRAS/MAPK signaling and disrupting cancer stem cell-associated plasticity. These findings, supported by both experimental and computational analyses, warrant further preclinical investigation of Alcea rosea-derived small molecules as potential therapeutics to overcome resistance in KRAS-driven pancreatic cancer.

Agreement on Use of Generative AI: Generative artificial intelligence was used exclusively to improve the language, grammar, and structure of text written by the authors. No AI tools were used in the study design, data collection, experimentation, analysis, interpretation of results, or preparation of the scientific content.

Citation Format:

Ruhban Ansar. Parry. Bioactive Compounds Derived from Alcea rosea Suppress KRAS-Driven Signaling and Cancer Stem Cell Plasticity in Pancreatic Ductal Adenocarcinoma [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B065.