Anti-cancer drugs · 2022
Mechanisms of GZ17-6.02 resistance.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Booth Laurence, West Cameron, Von Hoff Daniel, Dent Paul
Аннотация
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.
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.