Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen

Abstract

To overcome imatinib resistance, more potent ABL tyrosine kinase inhibitors (TKIs), such as nilotinib and dasatinib have been developed, with demonstrable preclinical activity against most imatinib-resistant BCR-ABL kinase domain mutations, with the exception of T315I. However, imatinib-resistant patients already harboring mutations have a higher likelihood of developing further mutations under the selective pressure of potent ABL TKIs. NVP-AUY922 (Novartis) is a novel 4,5-diaryloxazole adenosine triphosphate-binding site heat shock protein 90 (HSP90) inhibitor, which has been shown to inhibit the chaperone function of HSP90 and deplete the levels of HSP90 client protein including BCR-ABL. In this study, we investigated the combined effects of AUY922 and nilotinib on random mutagenesis for BCR-ABL mutation (Blood, 109; 5011, 2007). Compared with single agents, combination with AUY922 and nilotinib was more effective at reducing the outgrowth of resistant cell clones. No outgrowth was observed in the presence of 2 lM of nilotinib and 20 nM of AUY922. The observed data from the isobologram indicated the synergistic effect of simultaneous exposure to AUY922 and nilotinib even in BaF3 cells expressing BCR-ABL mutants including T315I. In vivo studies also demonstrated that the combination of AUY922 and nilotinib prolonged the survival of mice transplanted with mixture of BaF3 cells expressing wild-type BCR-ABL and mutant forms. Taken together, this study shows that the combination of AUY922 and nilotinib exhibits a desirable therapeutic index that can reduce the in vivo growth of mutant forms of BCR-ABL-expressing cells.

HSP90 inhibitor AUY922 abrogates up‐regulation of RTKs by mTOR inhibitor AZD8055 and potentiates its antiproliferative activity in human breast cancer

“…However, inactivation of HSP90 subsequently triggers a heat shock response that may attenuate the anticancer activity of HSP90 inhibitors. AUY922 has been studied to possess enhanced activity in combination with drugs with different targets in a wide spectrum of cancer types . We found that combination of mTOR kinase inhibitor with HSP90 inhibitor displayed synergistic effect against a panel of human breast cancer cells irrespective their ER, HER2 or PI3K status.…”

Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (Review)

“…Indeed, combination treatment with Hsp90 inhibitor IPI-504 and imatinib was more effective than either treatment alone in prolonging survival of mice simultaneously bearing both wild-type and T315I leukemic cells (131). Simultaneous exposure of BaF3 cells expressing BCR-ABL mutants including T315I to AUY922 and nilotinib was more effective at reducing the outgrowth of resistant cell clones as well as at survival prolongation of mice transplanted with mixture of BaF3 cells expressing wild-type BCR-ABL and mutant forms (132). Similarly, flavopiridol (semisynthetic flavone and selective inhibitor of CDKs) sensitized imatinibresistant HL/Bcr-Abl cells to GA and it seems that a cocktail of flavopiridol, 17-AAG (or its analogs) and imatinib may be an attractive approach for further investigations (133).…”

Systematic Identification of the HSP90 Regulated Proteome

“…Once such molecules become more widely available, proteome-wide profiling experiments such as the ones described here should help to define their specificities. HSP90 inhibition is also being considered in the context of combination therapies in order to suppress resistance formation by "oncogene switching" (2,45) or in order to extend the effective treatment time of targeted drugs such as kinase inhibitors (46). Our preliminary data using combinations of geldanamycin and the EGFR inhibitor lapatinib (Fig.…”