Heat 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.