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.
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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)
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Copyright | Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved. |
Chemical References |
- Antineoplastic Agents
- Histone Deacetylase Inhibitors
- Receptor, ErbB-2
- Receptor, ErbB-3
- Fluorouracil
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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
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