Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer
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 afte...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-10-01
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| Series: | Current Oncology |
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| Online Access: | https://www.mdpi.com/1718-7729/30/11/696 |
| _version_ | 1797459629300514816 |
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| author | Tej Tummala Ashley Sanchez Sevilla Uruchurtu Arielle De La Cruz Kelsey E. Huntington Andrew George Nicholas R. Liguori Leiqing Zhang Lanlan Zhou Abbas E. Abbas Christopher G. Azzoli Wafik S. El-Deiry |
| author_facet | Tej Tummala Ashley Sanchez Sevilla Uruchurtu Arielle De La Cruz Kelsey E. Huntington Andrew George Nicholas R. Liguori Leiqing Zhang Lanlan Zhou Abbas E. Abbas Christopher G. Azzoli Wafik S. El-Deiry |
| author_sort | Tej Tummala |
| collection | DOAJ |
| description | 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 lurbinectedin’s 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 the synergistic killing of pancreatic tumor cells. Western blot analysis of combination therapy indicates an upregulation of γH2AX, a DNA damage marker, and the Chk1/ATR pathway, which is 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 a highly efficient killing of tumor cells. Our results are developing insights regarding molecular mechanisms underlying the therapeutic efficacy of a novel combination drug treatment for pancreatic cancer. |
| first_indexed | 2024-03-09T16:55:04Z |
| format | Article |
| id | doaj.art-baef67e61ff84cad80cfd50ebbb42934 |
| institution | Directory Open Access Journal |
| issn | 1198-0052 1718-7729 |
| language | English |
| last_indexed | 2024-03-09T16:55:04Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Current Oncology |
| spelling | doaj.art-baef67e61ff84cad80cfd50ebbb429342023-11-24T14:37:05ZengMDPI AGCurrent Oncology1198-00521718-77292023-10-0130119611962610.3390/curroncol30110696Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic CancerTej Tummala0Ashley Sanchez Sevilla Uruchurtu1Arielle De La Cruz2Kelsey E. Huntington3Andrew George4Nicholas R. Liguori5Leiqing Zhang6Lanlan Zhou7Abbas E. Abbas8Christopher G. Azzoli9Wafik S. El-Deiry10Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02903, USALaboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02903, USALaboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02903, USALaboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02903, USALaboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02903, USALaboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02903, USALaboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02903, USALaboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02903, USALegorreta Cancer Center at Brown University, Providence, RI 02912, USALegorreta Cancer Center at Brown University, Providence, RI 02912, USALaboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02903, USAPancreatic 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 lurbinectedin’s 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 the synergistic killing of pancreatic tumor cells. Western blot analysis of combination therapy indicates an upregulation of γH2AX, a DNA damage marker, and the Chk1/ATR pathway, which is 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 a highly efficient killing of tumor cells. Our results are developing insights regarding molecular mechanisms underlying the therapeutic efficacy of a novel combination drug treatment for pancreatic cancer.https://www.mdpi.com/1718-7729/30/11/696lurbinectedin (ZEPZELCA™)irinotecan5-fluorouracil (5-FU)pancreatic cancercombination therapyγH2AX |
| spellingShingle | Tej Tummala Ashley Sanchez Sevilla Uruchurtu Arielle De La Cruz Kelsey E. Huntington Andrew George Nicholas R. Liguori Leiqing Zhang Lanlan Zhou Abbas E. Abbas Christopher G. Azzoli Wafik S. El-Deiry Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer Current Oncology lurbinectedin (ZEPZELCA™) irinotecan 5-fluorouracil (5-FU) pancreatic cancer combination therapy γH2AX |
| title | Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer |
| title_full | Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer |
| title_fullStr | Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer |
| title_full_unstemmed | Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer |
| title_short | Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer |
| title_sort | preclinical synergistic combination therapy of lurbinectedin with irinotecan and 5 fluorouracil in pancreatic cancer |
| topic | lurbinectedin (ZEPZELCA™) irinotecan 5-fluorouracil (5-FU) pancreatic cancer combination therapy γH2AX |
| url | https://www.mdpi.com/1718-7729/30/11/696 |
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