Abstract B137: Targeting MICAL2 sensitizes pancreatic cancer cells to gemcitabine and enhances therapeutic response
Ponmathi Panneerpandian, Kevin Christian Montecillo. Gulay, Mia MacDonald, Bharti Garg, Isabella Ng, Herve Tiriac, Andrew M. Lowy, Asimina CourelliAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, largely due to rapid development of resistance to standard chemotherapies such as gemcitabine. MICAL2 is a redox-dependent regulator of actin dynamics that is overexpressed in PDAC, but its role in therapeutic resistance remains poorly understood.
Methods:
Human and murine PDAC cell lines and patient-derived organoids were used to evaluate if MICAL2 function modulates response to chemotherapy. Inducible knockdown and overexpression systems were employed to manipulate MICAL2 levels. Response to gemcitabine was assessed using real-time proliferation (CellCyte), CellTiter-Glo viability assay, and colony formation assays following treatment. Cell cycle distribution was analyzed by flow cytometry. Induction of γH2AX was assessed by immunofluorescence and immunohistochemistry. In vivo efficacy of MICAL2 targeting in combination with chemotherapy was evaluated using PDAC xenograft models.
Results:
Inducible knockdown of MICAL2 significantly sensitized human and murine PDAC models, including patient-derived organoids, to gemcitabine. This was reflected by reduced proliferation (2.5-fold decrease, p<0.001), decreased viability (∼50%, p<0.005), and reduced clonogenic survival (∼65%, p<0.0001) compared to gemcitabine treatment alone. In contrast, MICAL2 overexpression conferred resistance, enhancing survival and colony formation during gemcitabine treatment. Combined MICAL2 knockdown and gemcitabine treatment increased S-phase/G2-M cell-cycle accumulation and enhanced γH2AX induction. In vivo studies showed that silencing MICAL2 expression in combination with gemcitabine produced the greatest reduction in tumor burden relative to all treatment groups.
Conclusion:
Reducing MICAL2 expression enhances gemcitabine efficacy by impairing proliferative recovery, promoting cell-cycle arrest, and increasing DNA damage. These findings support MICAL2 as a promising therapeutic target for overcoming chemotherapy resistance in pancreatic cancer.
Citation Format:
Ponmathi Panneerpandian, Kevin Christian Montecillo. Gulay, Mia MacDonald, Bharti Garg, Isabella Ng, Herve Tiriac, Andrew M. Lowy, Asimina Courelli. Targeting MICAL2 sensitizes pancreatic cancer cells to gemcitabine and enhances therapeutic response [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 B137.