A novel HSP90 inhibitor targeting the C-terminal domain attenuates trastuzumab resistance in HER2-positive breast cancer.

Molecular Cancer
Jung Min ParkJae Hong Seo

Abstract

Trastuzumab resistance in HER2-positive breast cancer is associated with a poorer prognosis. HSP90 is thought to play a major role in such resistance, but N-terminal inhibitors of this target have had little success. We sought to investigate the utility of NCT-547, a novel, rationally-designed C-terminal HSP90 inhibitor in the context of overcoming trastuzumab resistance. NCT-547 treatment significantly induced apoptosis without triggering the heat shock response (HSR), accompanied by caspase-3/- 7 activation in both trastuzumab-sensitive and -resistant cells. NCT-547 effectively promoted the degradation of full-length HER2 and truncated p95HER2, while also attenuating hetero-dimerization of HER2 family members. The impairment of cancer stem-like traits was observed with reductions in ALDH1 activity, the CD24low/CD44high subpopulation, and mammosphere formation in vitro and in vivo. NCT-547 was an effective inhibitor of tumor growth and angiogenesis, and no toxic outcomes were found in initial hepatic and renal analysis. Our findings suggest that NCT-547 may have applications in addressing trastuzumab resistance in HER2-positive breast cancer.

References

Apr 15, 2009·Molecular and Cellular Biology·Kim PedersenJoaquín Arribas
Dec 17, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Paula R PohlmannRay Mernaugh
Jun 15, 2012·Stem Cells·Eric BradleyGuanghu Wang
Jul 31, 2013·The Lancet Oncology·Rocio Garcia-CarboneroLuis Paz-Ares

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Methods Mentioned

BETA
immunoprecipitation
flow cytometry
xenograft
Assay
xenografts

Software Mentioned

Carl Zeiss
Dock
Surflex

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