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Anti-tumor activities of selective HSP90α/β inhibitor, TAS-116, in combination with bortezomib in multiple myeloma.

Suzuki R, Hideshima T, Mimura N, Minami J, Ohguchi H, Kikuchi S, Yoshida Y, Gorgun G, Cirstea D, Cottini F, Jakubikova J, Tai YT, Chauhan D, Richardson PG, Munshi NC, Utsugi T, Anderson KC - Leukemia (2014)

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.

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Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that interacts with various client proteins in eukaryotic cells: Akt (PI3K/Akt pathway), IL-6R (JAK/STAT pathway), Bcr-Abl (RAS/ERK pathway), CDK4, 6, 9 (cell cycling), and IκB kinases (NF-κB pathway)... The expression of HSP90 is upregulated (2- to 10-fold) in tumor cells compared with normal cells, reflecting multiple oncogenic pathways and maintenance of homeostasis within tumor cells... Significant degradation of HSP90 client proteins was triggered by TAS-116 in a dose-dependent manner in MM.1S cells (Supplementary Figure S1E)... Importantly, more significant degradation of phosho-C-Raf and phospho-MEK1/2, HSP90 client proteins and key RAS/RAF/MEK pathway regulators, was triggered by TAS-116 than 17-AAG in INA6 and NCI-H929 MM cells (Supplementary Figure S2D, 2E)... Taken together, these results indicate that TAS-116 induces cytotoxicity selectively and potently in MM cell lines and patient MM cells, even in NALM-6 cells, without toxicity in normal PBMNCs; potently targets HSP90 client proteins including C-Raf and MEK1/2; as well as inhibits upregulation of HSP27 and overcomes 17-AAG resistance mechanisms in MM cells... The OS was significantly prolonged in the combination group compared with either monotherapy cohort (P = .004 in TAS-116 vs the combination, and P = .0004 in BTZ vs the combination; Figure 1C)... These treatments were well tolerated, and no significant body weight loss was observed (Figure 1D)... In addition, we assessed the cytotoxicity of TAS-116 or HSP90 inhibitor PF-04928473 (SNX-2112) in combination with BTZ in ARPE-19 cells... Surprisingly, low-dose BTZ significantly ameliorated the cytotoxicity induced by TAS-116, compared with PF-04928473 (SNX-2112) (Figure 2B)... We next investigated the ocular toxicity profile of TAS-116 using an in vivo murine xenograft model... Importantly, TAS-116 15 mg/kg–treatment (maximum tolerated dose) did not induce ocular toxicity in mice, in contrast to PF-04929113 (SNX-5422) 40 mg/kg, which was associated with increased photoreceptor cell death in all retinal layers (Figure 2C)... TAS-116 also enhanced bortezomib (BTZ)-induced MM cytotoxicity, due to inhibition of BTZ-triggered canonical NF-κB activation and enhancing endoplasmic reticulum stress... We confirmed that TAS-116, alone and in combination with BTZ, was well tolerated; triggered significant tumor growth inhibition; and prolonged host survival in a murine xenograft model of human MM... Importantly, TAS-116 showed lower ocular toxicity, a known toxicity of HSP90 inhibitors, than PF-04929113 (SNX-5422)... Taken together, our studies show that TAS-116 blocks MM cell growth both in vitro and in vivo, and is well tolerated, providing the framework for its clinical evaluation to improve patient outcome in MM.

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TAS-116 is less toxic to human retinal pigment epithelial cells than other HSP90 inhibitors, and does not trigger ocular toxicity in mice(A) Human retinal pigment epithelial ARPE-19 cell lines and NCI-H929 MM cells were cultured with TAS-116 or 17-AAG (0–5 μM) for 48 hours. Cell viability was assessed by CellTiter-Glo® assay of triplicate cultures, expressed as percentage of untreated control. Data represent mean ± SD.(B) ARPE-19 cells were cultured for 48 hours with BTZ (0–2 nM) in combination with TAS-116 (0 μM: gray, 0.125 μM: gold, 0.25 μM: light orange, 0.5 μM: orange) or PF-04928473 (SNX-2112) (0 μM: gray, 0.125 μM: light green, 0.25 μM: sea green, 0.5 μM: green). Cell proliferation was assessed by CellTiter-Glo® assay of triplicate cultures, expressed as percentage of untreated control. Data represent mean ± SD. (* P < .01; ** P < .001)(C) TAS-116 (15 mg/kg; 5 days a week), PF-04929113 (SNX-5422) (40 mg/kg; 3 times per week), or vehicle were administered orally in SCID mice for two weeks. Retinal morphology and photoreceptor cell death were evaluated by TUNEL staining. ONL indicates outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer.
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Figure 2: TAS-116 is less toxic to human retinal pigment epithelial cells than other HSP90 inhibitors, and does not trigger ocular toxicity in mice(A) Human retinal pigment epithelial ARPE-19 cell lines and NCI-H929 MM cells were cultured with TAS-116 or 17-AAG (0–5 μM) for 48 hours. Cell viability was assessed by CellTiter-Glo® assay of triplicate cultures, expressed as percentage of untreated control. Data represent mean ± SD.(B) ARPE-19 cells were cultured for 48 hours with BTZ (0–2 nM) in combination with TAS-116 (0 μM: gray, 0.125 μM: gold, 0.25 μM: light orange, 0.5 μM: orange) or PF-04928473 (SNX-2112) (0 μM: gray, 0.125 μM: light green, 0.25 μM: sea green, 0.5 μM: green). Cell proliferation was assessed by CellTiter-Glo® assay of triplicate cultures, expressed as percentage of untreated control. Data represent mean ± SD. (* P < .01; ** P < .001)(C) TAS-116 (15 mg/kg; 5 days a week), PF-04929113 (SNX-5422) (40 mg/kg; 3 times per week), or vehicle were administered orally in SCID mice for two weeks. Retinal morphology and photoreceptor cell death were evaluated by TUNEL staining. ONL indicates outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer.

Mentions: Finally, we investigated the ocular toxicity profile of TAS-116, since ocular toxicity is one of the most notable toxicities limiting the clinical application of other HSP 90 inhibitors. Because others have shown that geldanamycin and its analogue 17-AAG inhibit proliferation of normal human retinal pigment epithelial ARPE-19 cells essential for the support of photoreceptors by inducing cell cycle arrest and apoptosis,15 we first examined the growth inhibitory effect of TAS-116 and 17-AAG in ARPE-19 cell line (Figure 2A). Importantly, TAS-116 was less toxic to ARPE-19 cells than 17-AAG. In addition, we assessed the cytotoxicity of TAS-116 or HSP90 inhibitor PF-04928473 (SNX-2112) in combination with BTZ in ARPE-19 cells. Surprisingly, low-dose BTZ significantly ameliorated the cytotoxicity induced by TAS-116, compared with PF-04928473 (SNX-2112) (Figure 2B). We next investigated the ocular toxicity profile of TAS-116 using an in vivo murine xenograft model. Importantly, TAS-116 15 mg/kg–treatment (maximum tolerated dose) did not induce ocular toxicity in mice, in contrast to PF-04929113 (SNX-5422) 40 mg/kg, which was associated with increased photoreceptor cell death in all retinal layers (Figure 2C). Taken together, these results indicate that TAS-116 demonstrates a safer ocular toxicity profile than PF-04929113 (SNX-5422).


Anti-tumor activities of selective HSP90α/β inhibitor, TAS-116, in combination with bortezomib in multiple myeloma.

Suzuki R, Hideshima T, Mimura N, Minami J, Ohguchi H, Kikuchi S, Yoshida Y, Gorgun G, Cirstea D, Cottini F, Jakubikova J, Tai YT, Chauhan D, Richardson PG, Munshi NC, Utsugi T, Anderson KC - Leukemia (2014)

TAS-116 is less toxic to human retinal pigment epithelial cells than other HSP90 inhibitors, and does not trigger ocular toxicity in mice(A) Human retinal pigment epithelial ARPE-19 cell lines and NCI-H929 MM cells were cultured with TAS-116 or 17-AAG (0–5 μM) for 48 hours. Cell viability was assessed by CellTiter-Glo® assay of triplicate cultures, expressed as percentage of untreated control. Data represent mean ± SD.(B) ARPE-19 cells were cultured for 48 hours with BTZ (0–2 nM) in combination with TAS-116 (0 μM: gray, 0.125 μM: gold, 0.25 μM: light orange, 0.5 μM: orange) or PF-04928473 (SNX-2112) (0 μM: gray, 0.125 μM: light green, 0.25 μM: sea green, 0.5 μM: green). Cell proliferation was assessed by CellTiter-Glo® assay of triplicate cultures, expressed as percentage of untreated control. Data represent mean ± SD. (* P < .01; ** P < .001)(C) TAS-116 (15 mg/kg; 5 days a week), PF-04929113 (SNX-5422) (40 mg/kg; 3 times per week), or vehicle were administered orally in SCID mice for two weeks. Retinal morphology and photoreceptor cell death were evaluated by TUNEL staining. ONL indicates outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer.
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Figure 2: TAS-116 is less toxic to human retinal pigment epithelial cells than other HSP90 inhibitors, and does not trigger ocular toxicity in mice(A) Human retinal pigment epithelial ARPE-19 cell lines and NCI-H929 MM cells were cultured with TAS-116 or 17-AAG (0–5 μM) for 48 hours. Cell viability was assessed by CellTiter-Glo® assay of triplicate cultures, expressed as percentage of untreated control. Data represent mean ± SD.(B) ARPE-19 cells were cultured for 48 hours with BTZ (0–2 nM) in combination with TAS-116 (0 μM: gray, 0.125 μM: gold, 0.25 μM: light orange, 0.5 μM: orange) or PF-04928473 (SNX-2112) (0 μM: gray, 0.125 μM: light green, 0.25 μM: sea green, 0.5 μM: green). Cell proliferation was assessed by CellTiter-Glo® assay of triplicate cultures, expressed as percentage of untreated control. Data represent mean ± SD. (* P < .01; ** P < .001)(C) TAS-116 (15 mg/kg; 5 days a week), PF-04929113 (SNX-5422) (40 mg/kg; 3 times per week), or vehicle were administered orally in SCID mice for two weeks. Retinal morphology and photoreceptor cell death were evaluated by TUNEL staining. ONL indicates outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer.
Mentions: Finally, we investigated the ocular toxicity profile of TAS-116, since ocular toxicity is one of the most notable toxicities limiting the clinical application of other HSP 90 inhibitors. Because others have shown that geldanamycin and its analogue 17-AAG inhibit proliferation of normal human retinal pigment epithelial ARPE-19 cells essential for the support of photoreceptors by inducing cell cycle arrest and apoptosis,15 we first examined the growth inhibitory effect of TAS-116 and 17-AAG in ARPE-19 cell line (Figure 2A). Importantly, TAS-116 was less toxic to ARPE-19 cells than 17-AAG. In addition, we assessed the cytotoxicity of TAS-116 or HSP90 inhibitor PF-04928473 (SNX-2112) in combination with BTZ in ARPE-19 cells. Surprisingly, low-dose BTZ significantly ameliorated the cytotoxicity induced by TAS-116, compared with PF-04928473 (SNX-2112) (Figure 2B). We next investigated the ocular toxicity profile of TAS-116 using an in vivo murine xenograft model. Importantly, TAS-116 15 mg/kg–treatment (maximum tolerated dose) did not induce ocular toxicity in mice, in contrast to PF-04929113 (SNX-5422) 40 mg/kg, which was associated with increased photoreceptor cell death in all retinal layers (Figure 2C). Taken together, these results indicate that TAS-116 demonstrates a safer ocular toxicity profile than PF-04929113 (SNX-5422).

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that interacts with various client proteins in eukaryotic cells: Akt (PI3K/Akt pathway), IL-6R (JAK/STAT pathway), Bcr-Abl (RAS/ERK pathway), CDK4, 6, 9 (cell cycling), and IκB kinases (NF-κB pathway)... The expression of HSP90 is upregulated (2- to 10-fold) in tumor cells compared with normal cells, reflecting multiple oncogenic pathways and maintenance of homeostasis within tumor cells... Significant degradation of HSP90 client proteins was triggered by TAS-116 in a dose-dependent manner in MM.1S cells (Supplementary Figure S1E)... Importantly, more significant degradation of phosho-C-Raf and phospho-MEK1/2, HSP90 client proteins and key RAS/RAF/MEK pathway regulators, was triggered by TAS-116 than 17-AAG in INA6 and NCI-H929 MM cells (Supplementary Figure S2D, 2E)... Taken together, these results indicate that TAS-116 induces cytotoxicity selectively and potently in MM cell lines and patient MM cells, even in NALM-6 cells, without toxicity in normal PBMNCs; potently targets HSP90 client proteins including C-Raf and MEK1/2; as well as inhibits upregulation of HSP27 and overcomes 17-AAG resistance mechanisms in MM cells... The OS was significantly prolonged in the combination group compared with either monotherapy cohort (P = .004 in TAS-116 vs the combination, and P = .0004 in BTZ vs the combination; Figure 1C)... These treatments were well tolerated, and no significant body weight loss was observed (Figure 1D)... In addition, we assessed the cytotoxicity of TAS-116 or HSP90 inhibitor PF-04928473 (SNX-2112) in combination with BTZ in ARPE-19 cells... Surprisingly, low-dose BTZ significantly ameliorated the cytotoxicity induced by TAS-116, compared with PF-04928473 (SNX-2112) (Figure 2B)... We next investigated the ocular toxicity profile of TAS-116 using an in vivo murine xenograft model... Importantly, TAS-116 15 mg/kg–treatment (maximum tolerated dose) did not induce ocular toxicity in mice, in contrast to PF-04929113 (SNX-5422) 40 mg/kg, which was associated with increased photoreceptor cell death in all retinal layers (Figure 2C)... TAS-116 also enhanced bortezomib (BTZ)-induced MM cytotoxicity, due to inhibition of BTZ-triggered canonical NF-κB activation and enhancing endoplasmic reticulum stress... We confirmed that TAS-116, alone and in combination with BTZ, was well tolerated; triggered significant tumor growth inhibition; and prolonged host survival in a murine xenograft model of human MM... Importantly, TAS-116 showed lower ocular toxicity, a known toxicity of HSP90 inhibitors, than PF-04929113 (SNX-5422)... Taken together, our studies show that TAS-116 blocks MM cell growth both in vitro and in vivo, and is well tolerated, providing the framework for its clinical evaluation to improve patient outcome in MM.

Show MeSH
Related in: MedlinePlus