Targeting BCL-XL in fibrolamellar hepatocellular carcinoma.

Abstract

Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal liver cancer with no proven effective systemic therapy. Inhibition of the antiapoptotic protein BCL-XL was found to synergize with a variety of systemic therapies in vitro using cells dissociated from patient-derived xenografts (PDX) of FLC or cells dissociated directly from surgical patient resections. As BCL-XL is physiologically expressed in platelets, prior efforts to leverage this vulnerability in other cancers have been hampered by severe thrombocytopenia. To overcome this toxicity, we treated FLC models with DT2216, a proteolysis targeting chimera (PROTAC) that directs BCL-XL for degradation via the von Hippel-Lindau (VHL) E3 ligase, which is minimally expressed in platelets. The combination of irinotecan and DT2216 in vitro on cells directly acquired from patients or in vivo using several xenografts derived from patients with FLC demonstrated remarkable synergy and at clinically achievable doses not associated with significant thrombocytopenia.

• Authors: Bassem Shebl, Denise Ng, Gadi Lalazar, Carly Rosemore, Tova M Finkelstein, Rachael D Migler, Guangrong Zheng, Peiyi Zhang, Caroline S Jiang, Adam Qureshi, Roger Vaughan, Mark Yarchoan, Ype P de Jong, Charles M Rice, Philip Coffino, Michael V Ortiz, Daohong Zhou, Sanford M Simon
• Journal: JCI insight (JCI Insight) Vol. 7 Issue 17 (09 08 2022) ISSN: 2379-3708 [Electronic] United States
• PMID: 36073545 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DT2216
• Piperazines

Topics

• Carcinoma, Hepatocellular (drug therapy)
• Humans
• Liver Neoplasms (drug therapy)
• Piperazines
• Thrombocytopenia