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bioRxiv · 10.1101/2023.09.13.557653

Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer

Tummala, T.·Uruchurtu, A. S. S.·De La Cruz, A.·Huntington, K. E.·George, A.·Liguori, N. R.·Zhang, L.·Zhou, L.·Abbas, A. E.·Azzoli, C. G.·El-Deiry, W. S.
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Abstract

Pancreatic cancer is a devastating disease with a poor prognosis. Novel chemotherapeutics in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin (PM01183; LY-01017) received FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types. Lurbinectedin stalls and degrades RNA Polymerase II and introduces breaks in DNA, causing subsequent apoptosis. We now demonstrate lurbinectedins highly efficient killing of human-derived pancreatic tumor cell lines PANC-1, BxPC-3, and HPAF-II as a single agent. We further demonstrate that a combination of lurbinectedin and irinotecan, a topoisomerase I inhibitor with FDA approval for advanced pancreatic cancer, results in synergistic killing of pancreatic tumor cells. Western blot analysis of combination therapy indicates an upregulation of {gamma}H2AX, a DNA damage marker, and the Chk1/ATR pathway, involved in replicative stress and DNA damage response. We further demonstrate that the triple combination between lurbinectedin, irinotecan, and 5-fluorouracil (5-FU) results in highly efficient killing of tumor cells. Our results are developing insights regarding molecular mechanisms underlying therapeutic efficacy of a novel combination drug treatment for pancreatic cancer.

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Tummala, T., Uruchurtu, A. S. S., De La Cruz, A., Huntington, K. E., George, A., Liguori, N. R., Zhang, L., Zhou, L., Abbas, A. E., Azzoli, C. G., El-Deiry, W. S.. 2023-09-17. Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer. https://doi.org/10.1101/2023.09.13.557653

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