Abstract
SummaryHeat shock protein 90 (Hsp90) is a molecular chaperone essential for the stability and function of multiple cellular client proteins, a number of which have been implicated in the pathogenesis of breast cancer. Here we undertook a comprehensive evaluation of the activity of ganetespib, a selective Hsp90 inhibitor, in this malignancy. With low nanomolar potency, ganetespib reduced cell viability in a panel of hormone receptor-positive, HER2-overexpressing, triple-negative and inflammatory breast cancer cell lines in vitro. Ganetespib treatment induced a rapid and sustained destabilization of multiple client proteins and oncogenic signaling pathways and even brief exposure was sufficient to induce and maintain suppression of HER2 levels in cells driven by this receptor. Indeed, HER2-overexpressing BT-474 cells were comparatively more sensitive to ganetespib than the dual HER2/EGFR tyrosine kinase inhibitor lapatinib in three-dimensional culture. Ganetespib exposure caused pleiotropic effects in the inflammatory breast cancer line SUM149, including receptor tyrosine kinases, MAPK, AKT and mTOR signaling, transcription factors and proteins involved in cell cycle, stress and apoptotic regulation, as well as providing combinatorial benefit with lapatinib in these cells. This multimodal activity translated to potent antitumor efficacy in vivo, suppressing tumor growth in MCF-7 and MDA-MB-231 xenografts and inducing tumor regression in the BT-474 model. Thus, ganetespib potently inhibits Hsp90 leading to the degradation of multiple clinically-validated oncogenic client proteins in breast cancer cells, encompassing the broad spectrum of molecularly-defined subtypes. This preclinical activity profile suggests that ganetespib may offer considerable promise as a new therapeutic candidate for patients with advanced breast cancers.Electronic supplementary materialThe online version of this article (doi:10.1007/s10637-013-9971-6) contains supplementary material, which is available to authorized users.
Highlights
Breast cancer remains the most commonly diagnosed female malignancy and principal cause of cancer-related mortality in women worldwide [1]
Ganetespib treatment resulted in a potent and robust dose-dependent destabilization of both isoforms of progesterone receptor (PR) (PR B and PR A) and estrogen receptor (ER). This was accompanied by increased HSP70 expression, which serves as a surrogate marker for Heat shock protein 90 (Hsp90) inhibition
Even a low 25 nM concentration of ganetespib resulted in measurable decreases in PR and ER expression levels by 6 h and these became more pronounced over time
Summary
Breast cancer remains the most commonly diagnosed female malignancy and principal cause of cancer-related mortality in women worldwide [1]. Gene expression profiling has resulted in the classification of human breast cancer into at least four subtypes based on discrete molecular signatures [3,4,5,6]. These include the luminal A and luminal B subtypes, which are positive for estrogen and progesterone receptors (ER and PR), human epidermal growth factor receptor 2 (HER2)-positive, and basal-like. Triple negative breast cancers (TNBC), an orphan grouping of tumors which lack expression of ER, PR and HER2, primarily fall into the basal-like subtype, the two definitions are not synonymous [7,8,9]
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