Antitumor efficacy of IPI-504, a selective heat shock protein 90 inhibitor against human epidermal growth factor receptor 2–positive human xenograft models as a single agent and in combination with trastuzumab or lapatinib

Abstract

IPI-504 is a novel, highly soluble small-molecule inhibitor of heat shock protein 90 (Hsp90), a protein chaperone essential for regulating homeostasis of oncoproteins and cell signaling proteins. Human epidermal growth factor receptor 2 (HER2; ErbB2) oncoprotein, expressed in a subset of metastatic breast cancers, is a Hsp90 client protein. In this study, we investigated the antitumor activity and the mechanism of action of IPI-504 in HER2 + , trastuzumabsensitive and trastuzumab-refractory cell lines in vitro and in vivo. IPI-504 exhibited potent antiproliferative activities (range of IC 50 , 10-40 nmol/L) against several tumor cell lines examined, whereby mechanism of action was mediated through HER2 and Akt degradation. Both intravenous and oral administration of IPI-504 assessed in multiple schedules showed potent tumor growth inhibition in vivo with corresponding degradation of HER2. The tolerability and efficacy of IPI-504 combined with either trastuzumab or lapatinib were also investigated in HER2 + tumor xenograft models. Combination of IPI-504 with trastuzumab significantly enhanced tumor growth delay and induced greater responses when compared with either agent alone. Although, as expected, trastuzumab alone did not exhibit any significant antitumor activity in the trastuzumab-resistant JIMT-1 model, IPI-504 administered in combination with trastuzumab yielded greater antitumor efficacy than either agent alone. Finally, combination of IPI-504 and lapatinib was well tolerated up to 50 mg/kg IPI-504 and 100 mg/kg lapatinib and resulted in significant delay in tumor growth, including partial and complete tumor responses. These lines of evidence support the development of IPI-504 in HER2-positive breast cancers as a single agent and in combination with either trastuzumab or lapatinib.

Antitumor Activity of the Hsp90 Inhibitor IPI-504 in HER2-Positive Trastuzumab-Resistant Breast Cancer

“…Similar results were observed in tumor models bearing the H1047R PI3K activating mutation or low levels of PTEN, known to be clinically confirmed mechanisms of intrinsic trastuzumab resistance (16,17). Furthermore, it has also been recently shown that IPI-504 reduces tumor growth of JIMT-1 xenografts, which are believed to be intrinsically resistant to trastuzumab because of upregulation of the membrane-associated mucin 4 (27). Taken together, these data suggest that IPI-504 treatment can counteract multiple trastuzumab-resistant mechanisms, which may offer a potential clinical path forward for intervention in this setting.…”

“…Both 17-AAG and IPI-504 have shown activity in multiple models of solid (e.g., lung, breast, pancreatic, and melanoma) and hematologic (e.g., chronic myelogenous leukemia and multiple myeloma) cancers (25)(26)(27)(28). In HER2-positive human breast cancer cell lines, IPI-504 potently downregulates HER2 and inhibits cell growth (27). IPI-504 is currently under clinical investigation in a phase I/II trial in combination with docetaxel that is focused on patients with non-small cell lung cancer.…”

HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium

“…Part 1 Clinical Trial Outcomes tant activities associated with HSP90 inhibition is the reversal of resistance to both trastuzumab and hormonal agents [305,306]. Importantly, there is preclinical data indicating that HSP90 inhibitors are synergistic with both trastuzumab [307][308][309] and lapatinib ditosylate [309,310]. Phase I and II clinical studies of first-generation HSP90 inhibitors have been published [311][312][313].…”

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

“…Combination of IPI-504 with transtuzumab significantly enhances tumor growth delay. 70 Combination of IPI-504 with lapatinib also enhances tumor growth delay. 70 The provirus integration site for Moloney murine leukemia virus tumor-specific cell surface antigens (PIM-1) is a proto-oncogene that encodes ser/thr kinase with multiple cellular functions.…”

“…70 Combination of IPI-504 with lapatinib also enhances tumor growth delay. 70 The provirus integration site for Moloney murine leukemia virus tumor-specific cell surface antigens (PIM-1) is a proto-oncogene that encodes ser/thr kinase with multiple cellular functions. Overexpression of PIM-1 has a critical role in the progression of prostatic and hematopoietic malignancies.…”