TY - JOUR
T1 - Overcoming Gemcitabine Resistance in Pancreatic Cancer Using the BCL-XL–Specific Degrader DT2216
AU - Thummuri, Dinesh
AU - Khan, Sajid
AU - Underwood, Patrick W.
AU - Zhang, Peiyi
AU - Wiegand, Janet
AU - Zhang, Xuan
AU - Budamagunta, Vivekananda
AU - Sobh, Amin
AU - Tagmount, Abderrahmane
AU - Loguinov, Alexander
AU - Riner, Andrea N.
AU - Akki, Ashwin S.
AU - Williamson, Elizabeth
AU - Hromas, Robert
AU - Vulpe, Christopher D.
AU - Zheng, Guangrong
AU - Trevino, Jose G.
AU - Zhou, Daohong
N1 - Funding Information:
The authors thank Alexandra M. Fahnlander for her editorial assistance. This study was supported in part by US National Institutes of Health (NIH) grants R01 CA242003 (to D. Zhou, J.G. Taverno, and G. Zheng), RO1 CA CA205224 (to R. Hromas) and T32 HG008958 (to A.N. Riner).
Funding Information:
D. Thummuri reports grants from the NIH during the conduct of the study and has a patent for Therapeutic Agents and Methods of Treatment pending and with royalties paid. S. Khan reports grants from University of Florida during the conduct of the study; and has a patent for BCL-2 Proteins Degraders for Cancer Treatment pending and with royalties paid. P. Zhang reports a patent for WO2020163823A2 issued, licensed, and with royalties paid from Dialectic Therapeutics and a patent for WO2019144117A1 issued, licensed, and with royalties paid from Dialectic Therapeutics. J. Wiegand reports grants from the NIH during the conduct of the study. X. Zhang reports a patent 1 pending and a patent 2 pending. A. Tagmount reports other support from University of Florida, College of Medicine Pilot Funds during the conduct of the study. A.N. Riner reports grants from the NIH during the conduct of the study. R. Hromas reports he has equity in Dialectic Therapeutics, which has licensed the compounds described herein. C.D. Vulpe reports other support from University of Florida, College of Medicine Pilot Funds during the conduct of the study. G. Zheng reports grants and other support
Publisher Copyright:
2021 The Authors; Published by the American Association for Cancer Research
PY - 2022/1
Y1 - 2022/1
N2 - Pancreatic cancer is the third most common cause of cancer-related deaths in the United States. Although gemcitabine is the standard of care for most patients with pancreatic cancer, its efficacy is limited by the development of resistance. This resistance may be attributable to the evasion of apoptosis caused by the overexpression of BCL-2 family antiapoptotic proteins. In this study, we investigated the role of BCL-XL in gemcitabine resistance to identify a combination therapy to more effectively treat pancreatic cancer. We used CRISPR-Cas9 screening to identify the key genes involved in gemcitabine resistance in pancreatic cancer. Pancreatic cancer cell dependencies on different BCL-2 family proteins and the efficacy of the combination of gemcitabine and DT2216 (a BCL-XL proteolysis targeting chimera or PROTAC) were determined by MTS, Annexin-V/PI, colony formation, and 3D tumor spheroid assays. The therapeutic efficacy of the combination was investigated in several patient-derived xenograft (PDX) mouse models of pancreatic cancer. We identified BCL-XL as a key mediator of gemcitabine resistance. The combination of gemcitabine and DT2216 synergistically induced cell death in multiple pancreatic cancer cell lines in vitro. In vivo, the combination significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice compared with the individual agents in pancreatic cancer PDX models. Their synergistic antitumor activity is attributable to DT2216-induced degradation of BCL-XL and concomitant suppression of MCL-1 by gemcitabine. Our results suggest that DT2216-mediated BCL-XL degradation augments the antitumor activity of gemcitabine and their combination could be more effective for pancreatic cancer treatment.
AB - Pancreatic cancer is the third most common cause of cancer-related deaths in the United States. Although gemcitabine is the standard of care for most patients with pancreatic cancer, its efficacy is limited by the development of resistance. This resistance may be attributable to the evasion of apoptosis caused by the overexpression of BCL-2 family antiapoptotic proteins. In this study, we investigated the role of BCL-XL in gemcitabine resistance to identify a combination therapy to more effectively treat pancreatic cancer. We used CRISPR-Cas9 screening to identify the key genes involved in gemcitabine resistance in pancreatic cancer. Pancreatic cancer cell dependencies on different BCL-2 family proteins and the efficacy of the combination of gemcitabine and DT2216 (a BCL-XL proteolysis targeting chimera or PROTAC) were determined by MTS, Annexin-V/PI, colony formation, and 3D tumor spheroid assays. The therapeutic efficacy of the combination was investigated in several patient-derived xenograft (PDX) mouse models of pancreatic cancer. We identified BCL-XL as a key mediator of gemcitabine resistance. The combination of gemcitabine and DT2216 synergistically induced cell death in multiple pancreatic cancer cell lines in vitro. In vivo, the combination significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice compared with the individual agents in pancreatic cancer PDX models. Their synergistic antitumor activity is attributable to DT2216-induced degradation of BCL-XL and concomitant suppression of MCL-1 by gemcitabine. Our results suggest that DT2216-mediated BCL-XL degradation augments the antitumor activity of gemcitabine and their combination could be more effective for pancreatic cancer treatment.
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UR - http://www.scopus.com/inward/citedby.url?scp=85122937130&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-21-0474
DO - 10.1158/1535-7163.MCT-21-0474
M3 - Article
C2 - 34667112
AN - SCOPUS:85122937130
VL - 21
SP - 184
EP - 192
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 1
ER -