Multifaceted Intervention by the Hsp90 Inhibitor Ganetespib (STA-9090) in Cancer Cells with Activated JAK/STAT Signaling

Abstract

There is accumulating evidence that dysregulated JAK signaling occurs in a wide variety of cancer types. In particular, mutations in JAK2 can result in the constitutive activation of STAT transcription factors and lead to oncogenic growth. JAK kinases are established Hsp90 client proteins and here we show that the novel small molecule Hsp90 inhibitor ganetespib (formerly STA-9090) exhibits potent in vitro and in vivo activity in a range of solid and hematological tumor cells that are dependent on JAK2 activity for growth and survival. Of note, ganetespib treatment results in sustained depletion of JAK2, including the constitutively active JAK2V617F mutant, with subsequent loss of STAT activity and reduced STAT-target gene expression. In contrast, treatment with the pan-JAK inhibitor P6 results in only transient effects on these processes. Further differentiating these modes of intervention, RNA and protein expression studies show that ganetespib additionally modulates cell cycle regulatory proteins, while P6 does not. The concomitant impact of ganetespib on both cell growth and cell division signaling translates to potent antitumor efficacy in mouse models of xenografts and disseminated JAK/STAT-driven leukemia. Overall, our findings support Hsp90 inhibition as a novel therapeutic approach for combating diseases dependent on JAK/STAT signaling, with the multimodal action of ganetespib demonstrating advantages over JAK-specific inhibitors.

Identification of Small Molecule Activators of the Janus Kinase/Signal Transducer and Activator of Transcription Pathway Using a Cell-Based Screen

“…Quercetin is found to inhibit the expression of heat shock protein 90 (Hsp90), whereas Hsp90 is involved in the regulation of JAK/STAT activation. 19,20) Thus, whether quercetin acts on the JAK/STAT pathway via Hsp90 needs to be further studied. Luteolin has also been found to have an antiviral effect and shows a synergistic effect with IFN-β in modulating the immune responses of peripheral blood mononuclear cells isolated from multiple sclerosis patients, thus, it is proposed as a promising adjuvant for multiple sclerosis therapy.…”

Ganetespib, a Unique Triazolone-Containing Hsp90 Inhibitor, Exhibits Potent Antitumor Activity and a Superior Safety Profile for Cancer Therapy

“…In the NCI-H1395 model, studies were conducted at the highest nonseverely toxic doses of 150 mg/kg weekly; in the MV4-11 model, animals were treated with ganetespib at 100 and 125 mg/kg weekly; in the MKN45 model, animals were treated with ganetespib at 50 mg/kg 3 times a week. Tumor growth inhibition was determined as described previously (24).…”

Preclinical Activity Profile and Therapeutic Efficacy of the HSP90 Inhibitor Ganetespib in Triple-Negative Breast Cancer

“…Tumor-bearing animals were also dosed with single agent or combination treatment using ganetespib and docetaxel (4 mg/kg) or paclitaxel (10 mg/ kg). Tumor growth inhibition was determined as described previously (23).…”

“…Because of its chemical design, ganetespib also lacks the characteristic hepatotoxicity that hampered the clinical application of the ansamycins. As predicted by its robust preclinical activity against a range of cancer models including lung, prostate, and leukemia (19)(20)(21)(22)(23), a maturing clinical profile has revealed clear evidence of therapeutic efficacy in human tumors, most notably in molecularly defined subsets of non-small cell lung cancer (NSCLC; ref. 24).…”