Efficacy and safety of TAS-116, an oral inhibitor of heat shock protein 90, in patients with metastatic or unresectable gastrointestinal stromal tumour refractory to imatinib, sunitinib and regorafenib: a phase II, single-arm trial

Doi, Toshihiko; Kurokawa, Yukinori; Sawaki, Akira; Ozaka, Masato; Takahashi, Tsuyoshi; Naito, Yoichi; Ohkubo, Shinji; Nishida, Toshirou

doi:10.1016/j.ejca.2019.08.009

Cited by 42 publications

(40 citation statements)

References 33 publications

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“…Failure of the first-generation agents was mostly attributed to insufficient dosing and resultant inadequate target inhibition. A new generation of HSP90 inhibitors with improved toxicities are under active clinical investigation as single drugs or in combination with other therapeutics in patients with various cancers, including lung [27,28], brain [29], and breast [30,31] cancers as well as sarcomas [32,33]. Docetaxel is being used as a first-line combination therapy for patients with HER-2 positive metastatic breast cancer [34].…”

Section: Discussionmentioning

confidence: 99%

HSP90 Inhibitor, 17-DMAG, Alone and in Combination with Lapatinib Attenuates Acquired Lapatinib-Resistance in ER-positive, HER2-Overexpressing Breast Cancer Cell Line

Lee

Shin

Kang

et al. 2020

Cancers

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Lapatinib, a Human Epidermal growth factor Receptor 2 (HER2)-targeting therapy in HER2-overexpressing breast cancer, has been widely used clinically, but the prognosis is still poor because most patients acquire resistance. Therefore, we investigated mechanisms related to lapatinib resistance to evaluate new therapeutic targets that may overcome resistance. Lapatinib-resistant cell lines were established using SKBR3 and BT474 cells. We evaluated cell viability and cell signal changes, gene expression and protein changes. In the xenograft mouse model, anti-tumor effects were evaluated using drugs. Analysis of the protein interaction network in two resistant cell lines with different lapatinib resistance mechanisms showed that HSP90 protein was commonly increased. When Heat Shock Protein 90 (HSP90) inhibitors were administered alone to both resistant cell lines, cell proliferation and protein expression were effectively inhibited. However, inhibition of cell proliferation and protein expression with a combination of lapatinib and HSP90 inhibitors showed a more synergistic effect in the LR-BT474 cell line than the LR-SKBR3 cell line, and the same result was exhibited with the xenograft model. These results suggest that HSP90 inhibitors in patients with lapatinib-resistant Estrogen Receptor (ER) (+) HER2 (+) breast cancer are promising therapeutics for future clinical trials.

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Section: Discussionmentioning

confidence: 99%

HSP90 Inhibitor, 17-DMAG, Alone and in Combination with Lapatinib Attenuates Acquired Lapatinib-Resistance in ER-positive, HER2-Overexpressing Breast Cancer Cell Line

Lee

Shin

Kang

et al. 2020

Cancers

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“…Additionally, the viability of both H1975‐LR/TM and PC9‐COR cells was compromised by treatment with the HSP90 inhibitor (Figure 4(b) and Figure 5(b)). Importantly, TAS‐116 was highly active against these cell lines at therapeutic concentrations of 1–3 μM 33,34 . In contrast, the combination efficacy of TAS‐121 and TAS‐116 was not observed in both the H1975 and H1975‐LR/TM cell lines (Figure S1).…”

Section: Resultsmentioning

confidence: 99%

“…TAS‐116 possesses a distinct advantage over other HSP90 inhibitors, as its distribution in retinal tissue is lower than that in plasma, and it is rapidly eliminated from the retina 27 . Indeed, eye disorders were not clinically significant in trials for patients with advanced solid tumors 33,34 . Therefore, further studies should focus on TAS‐116 as a promising therapeutic option for EGFR ‐mutated lung cancer.…”

Section: Discussionmentioning

confidence: 99%

HSP90 inhibition overcomes EGFR amplification‐induced resistance to third‐generation EGFR‐TKIs

Watanabe

Goto²,

Yasuda

et al. 2021

Thoracic Cancer

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Background Patients with non‐small cell lung cancer (NSCLC) harboring activating EGFR mutations are sensitive to epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) but inevitably develop resistance to the inhibitors mostly through acquisition of the secondary T790M mutation. Although third‐generation EGFR‐TKIs overcome this resistance by selectively inhibiting EGFR with EGFR‐TKI‐sensitizing and T790M mutations, acquired resistance to third‐generation EGFR‐TKIs invariably develops. Methods Next‐generation sequencing (NGS) and fluorescence in situ hybridization (FISH) analysis were performed in an EGFR T790M‐mutated NSCLC patient who had progressed after a third‐generation EGFR‐TKI, TAS‐121. EGFR‐mutated cell lines were subjected to a cell proliferation assay and western blotting analysis with EGFR‐TKIs and a heat shock protein 90 (HSP90) inhibitor. Results NGS and FISH analysis revealed EGFR amplification in the resistant cancer cells. While EGFR L858R/T90M‐mutated cell line was sensitive to osimertinib or TAS‐121 in vitro, EGFR‐overexpressing cell lines displayed resistance to these EGFR‐TKIs. Western blot analysis showed that EGFR phosphorylation and overexpression of EGFR in cell lines was not suppressed by third‐generation EGFR‐TKIs. In contrast, an HSP90 inhibitor reduced total and phosphorylated EGFR and inhibited the proliferation of resistant cell lines. Conclusions EGFR amplification confers resistance to third‐generation EGFR‐TKIs which can be overcome by HSP90 inhibition. The results provide a preclinical rationale for the use of HSP90 inhibitors to overcome EGFR amplification‐mediated resistance.

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“…We note that although TAS-116 is not as potent as other HSP90 inhibitors tested, it is selective for HSP90α and HSP90β (61) in cytosol/nucleus and does not target GRP94 in ER and TRAP1 in mitochondria. In addition, unlike the other HSP90 inhibitors, TAS-116 is an oral drug that is currently in a Phase 3 clinical trial of gastrointestinal stromal cancer (GIST) (78,79). The promising effect of HSP90 inhibition and HSP70 overexpression provides a basis for further investigations of protein chaperones in the treatment of NPC1 disease.…”

Section: Discussionmentioning

confidence: 99%

HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts

Pipalia

Saad

Subramanian

et al. 2021

Preprint

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Niemann Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder caused by mutations of the NPC1 gene. More than 300 disease-associated mutations are reported in patients, resulting in abnormal accumulation of unesterified cholesterol, glycosphingolipids and other lipids in late endosomes and lysosomes (LE/Ly) of many cell types. Previously, we showed that treatment of many different NPC1 mutant fibroblasts with histone deacetylase inhibitors resulted in reduction of cholesterol storage, and we found that this was associated with enhanced exit of the NPC1 protein from the endoplasmic reticulum and delivery to LE/Ly. This suggested that histone deacetylase inhibitors may work through changes in protein chaperones to enhance the folding of NPC1 mutants, allowing them to be delivered to LE/Ly. In this study, we evaluated the effect of several HSP90 inhibitors on NPC1I1061T skin fibroblasts. We found that HSP90 inhibition resulted in the clearance of cholesterol from LE/Ly, and this was associated with enhanced delivery of the mutant NPC1I1061T protein to LE/Ly. We also observed that inhibition of HSP90 increased the expression of HSP70, and overexpression of HSP70 also reduced cholesterol storage in NPC1I1061T fibroblasts. However, we did not see the correction of cholesterol storage by arimoclomol, a drug that is reported to increase HSP70 expression, at doses up to 0.5 mM. These results indicate that manipulation of molecular chaperones may lead to effective treatments for NPC1 disease, but further investigation of mechanisms will be required.

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Efficacy and safety of TAS-116, an oral inhibitor of heat shock protein 90, in patients with metastatic or unresectable gastrointestinal stromal tumour refractory to imatinib, sunitinib and regorafenib: a phase II, single-arm trial

Cited by 42 publications

References 33 publications

HSP90 Inhibitor, 17-DMAG, Alone and in Combination with Lapatinib Attenuates Acquired Lapatinib-Resistance in ER-positive, HER2-Overexpressing Breast Cancer Cell Line

HSP90 Inhibitor, 17-DMAG, Alone and in Combination with Lapatinib Attenuates Acquired Lapatinib-Resistance in ER-positive, HER2-Overexpressing Breast Cancer Cell Line

HSP90 inhibition overcomes EGFR amplification‐induced resistance to third‐generation EGFR‐TKIs

HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts

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