Wee1-Hsp90 inhibitor combination treatment: molecular therapy with potentially broad applicability.

Pharmacological inhibition of molecular chaperone Hsp90 is an attractive approach for anticancer therapy, since the chaperone activity of Hsp90 is critical for the stability and activity of a variety of cellular client proteins. The list of Hsp90 client proteins is always expanding and includes transcription factors, steroid hormone receptors, protein kinases, oncogenes, proto-oncogenes and signaling molecules.1,2 Since many of these client proteins promote tumor growth, metastasis and angiogenesis, inhibition of Hsp90 can be the “one punch” that cripples the tumorigenic and metastatic potential of tumors regardless of their tissue or cellular origin. Hsp90 inhibitors have been combined with a variety of chemotherapy and targeted treatment drugs, but the rationale for such combinations is largely empirical. The study by Iwai et al. not only demonstrates potent synergistic antitumor activity upon combining a Wee1 kinase inhibitor and several Hsp90 inhibitors, but the rationale for simultaneous inhibition of Wee1 kinase and Hsp90 is based on the elegant mechanistic data that have been previously published by this group.3-5 Wee1 is a cell cycle-dependent kinase that is essential for the G2-M checkpoint. While hyperactivity of Wee1 kinase causes cell cycle arrest in the G2-M phase, its inhibition causes premature mitotic entry and cell death.6 Wee1 is a client protein of Hsp90. More importantly, Wee1 (Swe1 in yeast) kinase phosphorylates a conserved tyrosine residue in Hsp90 (Y38 in human Hsp90α; Y24 in yeast Hsp90).4,5 Wee1 targets and phosphorylates Hsp90 while it is in an “open” conformation, and reversible phosphorylation is important for its ability to chaperone a number of clients, including several oncogenic kinases.3-5,7 Further, Hsp90 inhibitors bind less efficiently to phosphorylated Hsp90, hence inhibition of Wee1 enhances drug binding to Hsp90 and makes cells more sensitive to Hsp90 inhibitors. The discovery of Wee1-mediated phosphorylation of Hsp90 and its functional consequences provides the rationale for combining a Wee1 inhibitor with an HsP90 inhibitor as a novel anticancer combination therapy. This group previously reported that pharmacological inhibition of Wee1 and its molecular silencing with siRNA uniformly increased apoptotic activity of the Hsp90 inhibitor 17-AAG in vitro.5 The current study by Iwai et al. demonstrates that Wee1 inhibition synergizes with any one of several clinically evaluated Hsp90 inhibitors to inhibit cell growth in yeast and in an androgen-independent and invasive human prostate carcinoma cell line, PC3.3 The fact that 17-AAG, SNX-2112 and STA-9090 (ganetespib) are currently in clinical trials and synergize with a Wee1 inhibitor (Inhibitor II) suggests that Wee1-Hsp90 inhibitor combination therapy may be translatable to the clinic. One of the intriguing features of the study is that the drug combination not only inhibits Wee1 activity, but also transcriptionally downregulates it. It is possible that in a feedback loop, the drug combination causes sustained downregulation of Wee1, which, in turn, achieves sustained tempering of Hsp90 chaperone activity and downregulation of several Hsp90-dependent signaling pathways related to protection from apoptosis and DNA damage. The unique gene signature and enhanced apoptotic signaling induced by Wee1 inhibitor/Hsp90 inhibitor combination can be further confirmed by combining an Hsp90 inhibitor with another Wee1-inhibitor (e.g., MK-1775).6 Nevertheless, the Iwai et al. study shows that combined Wee1-Hsp90 inhibition may be an effective targeted therapy based on clearly defined molecules that are critical for cancer growth and progression. Consistent with this theme, the PC3 xenograft study corroborates the in vitro observations regarding the potent antitumor activity of this drug combination and confirms the molecular events responsible for the observed enhanced antitumor activity. Clinical applicability of such a strategy is substantial, since effective targeting of Hsp90 should be efficacious against a variety of tumors and high expression of Wee1 is associated with poor disease-free survival in certain cancers.8 Further, based on the reported gene signature, this drug combination may also synergize with standard DNA damaging drugs. Therefore, future studies to evaluate bioavailability, toxicity, dosing sequence and schedule are needed to support clinical trials of this mechanism-based novel combination therapy.