Superior Efficacy and Selectivity of Novel Small-Molecule Kinase Inhibitors of T790M-Mutant EGFR in Preclinical Models of Lung Cancer

Rho, Jin Kyung; Lee, In Young; Choi, Yun Jung; Choi, Chang‐Min; Hur, Jae-Young; Koh, Jai‐Kyoung; Lee, Jaekyoo; Suh, Beomseok; Song, Ho-Juhn; Salgaonkar, Paresh; Lee, Jungmi; Lee, Jaesang; Jung, Dong Sik; Kim, Sangjin; Woo, Dong‐Cheol; Baek, In-Jeoung; Lee, Joo‐Yong; Ha, Chang Hoon; Sung, Young Hoon; Kim, Jeong Kon; Kim, Woo Sung; Song, Joon Seon; Kim, Cheol Hyeon; Bivona, Trever G.; Lee, Jae Cheol

doi:10.1158/0008-5472.can-16-2432

Cited by 13 publications

(11 citation statements)

References 39 publications

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“…Next, we examined the effect of vorinostat on gefitinib sensitivity in PC9 and PC9GR cells. In accordance with previous reports (8,9), treatment with 0.01 µM gefitinib alone significantly decreased the viability of PC9 cells, but it had no effect on PC9GR cells ( Fig. 2A, upper graphs).…”

Section: Resultssupporting

confidence: 93%

“…First, we examined the inhibitory effect of the HDACI vorinostat on the viability of NSCLC PC9 and gefitinib-resistant PC9GR cells using a CellTiter-Glo assay. The PC9 cell line has a deletional mutation in EGFR exon 19 and the PC9GR cell line is resistant to gefitinib by having acquired a secondary T790M mutation in EGFR exon 20 (8,9). Exposure to vorinostat efficiently reduced the viability of both cell lines in a concentration-dependent manner (Fig.…”

Section: Resultsmentioning

confidence: 93%

“…Cell culture and reagents. The human NSCLC cell line PC9 and gefitinib-resistant PC9 (PC9GR) cells were provided by Dr Rho (Asan Medical Center, Seoul, Korea) (8,9). All cell lines were cultured in Gibco ® RPMI-1640 medium (Thermo Fisher Scientific, Inc., Waltham, MA, USA) containing 10% fetal bovine serum (FBS; Gibco; Thermo Fisher Scientific, Inc.) and 1% penicillin/streptomycin (Gibco; Thermo Fisher Scientific, Inc.) at 37˚C in an atmosphere containing 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

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Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation

Park

Kim

et al. 2018

Oncol Rep

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Although different mechanisms of acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have been reported in non-small cell lung cancers (NSCLCs), the optimal treatment for patients with acquired resistance has not been clearly defined. The purpose of this study was to investigate the antitumor effects of gefitinib in combination with vorinostat, a potent histone deacetylase inhibitor (HDACI), and their associated molecular mechanisms in relation to activating apoptosis in NSCLC. The treatment using a combination of vorinostat and gefitinib was more potent in promoting cell death by activating apoptosis than gefitinib alone in parental PC9 cells that harbor an EGFR-activating mutation (EGFR exon 19 deletion) and gefitinib-resistant PC9 cells (PC9GR) with an EGFR T790M mutation. This combination induced heat shock protein 90 (HSP90) cleavage and reduced the level of HSP90 client proteins, including EGFR, MET and AKT, in PC9 and PC9GR cells. The addition of 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride, a scavenger of reactive oxygen species (ROS), inhibited the degradation of HSP90 client proteins and HSP90 cleavage that was induced by co-treatment as well as the cleavage of caspase-3, caspase-8, and caspase-9 and cell death. We also observed that cleavage of HSP90 and its clients were blocked when caspases were inhibited. These results revealed that co-treatment with vorinostat and gefitinib induced ROS-dependent caspase activation, leading to the downregulation of HSP90 clients through HSP90 cleavage. Collectively, our findings provide a new basis for strategies that combine vorinostat with an EGFR-TKI to reverse EGFR-TKI resistance in NSCLC.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

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Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation

Park

Kim

et al. 2018

Oncol Rep

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“…We previously described a third‐generation EGFR‐TKI (GNS compound) which is similar to osimertinib in terms of its effects on EGFR‐mutant cell lines, xenograft models and selectivity of kinases, but showed a superior intracranial antitumor efficacy (Rho et al ., ). In our analyses in that study, osimertinib as well as GNS compound at 10 mg·kg −1 showed a good response initially, but this was not sustained over time in most of the mice.…”

Section: Discussionmentioning

confidence: 97%

“…We next tested whether the intrathecal injection of NUFS-sErt could efficiently suppress the growth of intracranial HCC827-Luc tumors. We established a mouse model with a HCC827-Luc intracranial xenograft in the left brain, as described previously (Rho et al, 2017). We fixed a screwing device into the right brain ventricles of these animals to enable intrathecal drug injection (Fig.…”

Section: Efficacy Of Nufs-sert In Vivomentioning

confidence: 99%

Efficacy of nano‐particulated, water‐soluble erlotinib against intracranial metastases of EGFR‐mutant lung cancer

et al. 2018

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Central nervous system (CNS) metastasis is one of the serious complications of epidermal growth factor receptor (EGFR)‐mutant lung cancer, which arises due to poor penetration of the brain–blood barrier by EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs). Although osimertinib, a third‐generation EGFR‐TKI, has efficacy against CNS metastases, further treatment modalities are still needed as some of these lesions do not respond to osimertinib, or undergo progression after an initial response to this drug if radiotherapy has already been conducted. Here, we investigated the efficacy of water‐soluble erlotinib (NUFS‐sErt) against these metastases. This agent was synthesized using a nano‐particulation platform technology utilizing fat and supercritical fluid (NUFS™) to resolve the low solubility problem that typically prevents the creation of injectable forms of EGFR‐TKIs. The average NUFS‐sErt particle size was 236.4 nm, and it showed time‐dependent dissolution in culture media. The effects of NUFS‐sErt were similar to those of conventional erlotinib in terms of inhibiting the proliferation of EGFR‐mutant lung cancer cells and suppressing EGFR signaling. In an intraperitoneal xenograft model of HCC827 cells, intraperitoneal administration of NUFS‐sErt produced a dose‐dependent inhibition of tumor growth and enhanced survival rate. Notably, the injection of NUFS‐sErt into the brain ventricle caused significant tumor growth inhibition in an intracranial xenograft model. Hence, our current findings indicate that NUFS‐sErt is a novel, water‐soluble form of erlotinib that can be administered using intraventricular or intrathecal injections. The target cases would be patients with a progressive CNS metastasis and no other therapeutic options. This drug could also be given intravenously to patients with swallowing difficulties or an inability to ingest due to a medical condition.

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Discovery of a Potent and Mutant-Selective EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Lung Cancer

et al. 2018

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Superior Efficacy and Selectivity of Novel Small-Molecule Kinase Inhibitors of T790M-Mutant EGFR in Preclinical Models of Lung Cancer

Cited by 13 publications

References 39 publications

Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation

Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation

Efficacy of nano‐particulated, water‐soluble erlotinib against intracranial metastases of EGFR‐mutant lung cancer

Discovery of a Potent and Mutant-Selective EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Lung Cancer

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