Mechanisms of GZ17-6.02 resistance.

Abstract

OBJECTIVES:

The drug GZ17-6.02 is undergoing phase I in solid tumor patients (NCT03775525). The present studies initially determined the impact of prolonged exposure of colorectal tumors to GZ17-6.02, and to determine whether GZ17-6.02 enhanced the efficacy of an anti-PD1 antibody. Subsequently, studies defined the evolutionary resistance mechanisms in tumor cells previously exposed to GZ17-6.02.

METHODS:

IACUC-approved animal studies were performed. In cell immunoblotting, cell transfections and trypan blue death assays were performed.

RESULTS:

Prolonged exposure of colorectal tumors to GZ17-6.02 enhanced the efficacy of 5-fluorouracil and of an anti-PD1 antibody, significantly prolonging animal survival. Tumor cells previously exposed to GZ17-6.02 in vivo had elevated their expression of ERBB2 and ERBB3, and increased phosphorylation of ERBB1, ERBB3, PDGFRβ, AKT T308, ERK1/2, p70 S6K T389, STAT5 Y694 and c-SRC Y416. The phosphorylation of c-SRC Y527 declined. The efficacy of ERBB receptor inhibitors at killing these resistant tumor cells was unaltered by prior GZ17-6.02 exposure whereas the efficacy of multi-kinase/PDGFRβ inhibitors was significantly reduced. Treatment of colon cancer cells with GZ17-6.02 rapidly reduced the levels of multiple HDAC proteins and altered their subcellular localization. Isolates from resistant tumors expressed less CD95 and FAS-L. HDAC inhibitors enhanced CD95 and FAS-L levels in the resistant cells via activation of NFκB and HDAC inhibitors restored the efficacy of GZ17-6.02 to near control levels.

CONCLUSIONS:

Our findings demonstrate that GZ17-6.02 has the potential to be developed as a colon cancer therapeutic and that resistance to the drug can be partially reversed by HDAC inhibitors.

• Authors: Laurence Booth, Cameron West, Daniel Von Hoff, Paul Dent
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 33 Issue 5 Pg. 415-423 (06 01 2022) ISSN: 1473-5741 [Electronic] England
• PMID: 35276694 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Receptor, ErbB-2
• Receptor, ErbB-3
• Fluorouracil

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Clinical Trials, Phase I as Topic
• Colonic Neoplasms (drug therapy, genetics)
• Fluorouracil
• Histone Deacetylase Inhibitors
• Humans
• Receptor, ErbB-2
• Receptor, ErbB-3