The Experts below are selected from a list of 1554 Experts worldwide ranked by ideXlab platform
Seiji Yano - One of the best experts on this subject based on the ideXlab platform.
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histone deacetylase 3 inhibition overcomes bim deletion polymorphism mediated Osimertinib resistance in egfr mutant lung cancer
Clinical Cancer Research, 2017Co-Authors: Azusa Tanimoto, Tadaaki Yamada, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Xavier Roca, Seiji YanoAbstract:Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non–small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against Osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism. Experimental Design: We used EGFR -mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of Osimertinib in vitro and in vivo . Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR. Results: EGFR -mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to Osimertinib in a polymorphism dosage–dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion–positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in Osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with Osimertinib could regress tumors in EGFR -mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR -T790M mutations. Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with Osimertinib, for treating EGFR -mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139–49. ©2016 AACR .
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histone deacetylase 3 inhibition overcomes bim deletion polymorphism mediated Osimertinib resistance in egfr mutant lung cancer
Clinical Cancer Research, 2017Co-Authors: Azusa Tanimoto, Tadaaki Yamada, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Xavier Roca, Tiong S Ong, Seiji YanoAbstract:Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non-small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against Osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism.Experimental Design: We used EGFR-mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of Osimertinib in vitro and in vivo Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR.Results:EGFR-mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to Osimertinib in a polymorphism dosage-dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion-positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in Osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with Osimertinib could regress tumors in EGFR-mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR-T790M mutations.Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with Osimertinib, for treating EGFR-mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139-49. ©2016 AACR.
Azusa Tanimoto - One of the best experts on this subject based on the ideXlab platform.
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axl confers intrinsic resistance to Osimertinib and advances the emergence of tolerant cells
Nature Communications, 2019Co-Authors: Hirokazu Taniguchi, Tadaaki Yamada, Rong Wang, Keiko Tanimura, Yuta Adachi, Akihiro Nishiyama, Azusa Tanimoto, Shinji Takeuchi, Luiz H AraujoAbstract:A novel EGFR-tyrosine kinase inhibitor (TKI), Osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to Osimertinib. This study showed that Osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to Osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to Osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to Osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to Osimertinib and the emergence of Osimertinib-tolerant cells.
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histone deacetylase 3 inhibition overcomes bim deletion polymorphism mediated Osimertinib resistance in egfr mutant lung cancer
Clinical Cancer Research, 2017Co-Authors: Azusa Tanimoto, Tadaaki Yamada, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Xavier Roca, Seiji YanoAbstract:Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non–small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against Osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism. Experimental Design: We used EGFR -mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of Osimertinib in vitro and in vivo . Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR. Results: EGFR -mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to Osimertinib in a polymorphism dosage–dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion–positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in Osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with Osimertinib could regress tumors in EGFR -mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR -T790M mutations. Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with Osimertinib, for treating EGFR -mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139–49. ©2016 AACR .
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histone deacetylase 3 inhibition overcomes bim deletion polymorphism mediated Osimertinib resistance in egfr mutant lung cancer
Clinical Cancer Research, 2017Co-Authors: Azusa Tanimoto, Tadaaki Yamada, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Xavier Roca, Tiong S Ong, Seiji YanoAbstract:Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non-small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against Osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism.Experimental Design: We used EGFR-mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of Osimertinib in vitro and in vivo Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR.Results:EGFR-mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to Osimertinib in a polymorphism dosage-dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion-positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in Osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with Osimertinib could regress tumors in EGFR-mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR-T790M mutations.Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with Osimertinib, for treating EGFR-mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139-49. ©2016 AACR.
Tadaaki Yamada - One of the best experts on this subject based on the ideXlab platform.
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axl confers intrinsic resistance to Osimertinib and advances the emergence of tolerant cells
Nature Communications, 2019Co-Authors: Hirokazu Taniguchi, Tadaaki Yamada, Rong Wang, Keiko Tanimura, Yuta Adachi, Akihiro Nishiyama, Azusa Tanimoto, Shinji Takeuchi, Luiz H AraujoAbstract:A novel EGFR-tyrosine kinase inhibitor (TKI), Osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to Osimertinib. This study showed that Osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to Osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to Osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to Osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to Osimertinib and the emergence of Osimertinib-tolerant cells.
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histone deacetylase 3 inhibition overcomes bim deletion polymorphism mediated Osimertinib resistance in egfr mutant lung cancer
Clinical Cancer Research, 2017Co-Authors: Azusa Tanimoto, Tadaaki Yamada, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Xavier Roca, Seiji YanoAbstract:Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non–small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against Osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism. Experimental Design: We used EGFR -mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of Osimertinib in vitro and in vivo . Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR. Results: EGFR -mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to Osimertinib in a polymorphism dosage–dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion–positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in Osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with Osimertinib could regress tumors in EGFR -mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR -T790M mutations. Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with Osimertinib, for treating EGFR -mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139–49. ©2016 AACR .
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histone deacetylase 3 inhibition overcomes bim deletion polymorphism mediated Osimertinib resistance in egfr mutant lung cancer
Clinical Cancer Research, 2017Co-Authors: Azusa Tanimoto, Tadaaki Yamada, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Xavier Roca, Tiong S Ong, Seiji YanoAbstract:Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non-small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against Osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism.Experimental Design: We used EGFR-mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of Osimertinib in vitro and in vivo Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR.Results:EGFR-mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to Osimertinib in a polymorphism dosage-dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion-positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in Osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with Osimertinib could regress tumors in EGFR-mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR-T790M mutations.Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with Osimertinib, for treating EGFR-mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139-49. ©2016 AACR.
Shinji Takeuchi - One of the best experts on this subject based on the ideXlab platform.
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axl confers intrinsic resistance to Osimertinib and advances the emergence of tolerant cells
Nature Communications, 2019Co-Authors: Hirokazu Taniguchi, Tadaaki Yamada, Rong Wang, Keiko Tanimura, Yuta Adachi, Akihiro Nishiyama, Azusa Tanimoto, Shinji Takeuchi, Luiz H AraujoAbstract:A novel EGFR-tyrosine kinase inhibitor (TKI), Osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to Osimertinib. This study showed that Osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to Osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to Osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to Osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to Osimertinib and the emergence of Osimertinib-tolerant cells.
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histone deacetylase 3 inhibition overcomes bim deletion polymorphism mediated Osimertinib resistance in egfr mutant lung cancer
Clinical Cancer Research, 2017Co-Authors: Azusa Tanimoto, Tadaaki Yamada, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Xavier Roca, Seiji YanoAbstract:Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non–small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against Osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism. Experimental Design: We used EGFR -mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of Osimertinib in vitro and in vivo . Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR. Results: EGFR -mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to Osimertinib in a polymorphism dosage–dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion–positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in Osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with Osimertinib could regress tumors in EGFR -mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR -T790M mutations. Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with Osimertinib, for treating EGFR -mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139–49. ©2016 AACR .
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histone deacetylase 3 inhibition overcomes bim deletion polymorphism mediated Osimertinib resistance in egfr mutant lung cancer
Clinical Cancer Research, 2017Co-Authors: Azusa Tanimoto, Tadaaki Yamada, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Xavier Roca, Tiong S Ong, Seiji YanoAbstract:Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non-small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against Osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism.Experimental Design: We used EGFR-mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of Osimertinib in vitro and in vivo Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR.Results:EGFR-mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to Osimertinib in a polymorphism dosage-dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion-positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in Osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with Osimertinib could regress tumors in EGFR-mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR-T790M mutations.Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with Osimertinib, for treating EGFR-mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139-49. ©2016 AACR.
Xavier Roca - One of the best experts on this subject based on the ideXlab platform.
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histone deacetylase 3 inhibition overcomes bim deletion polymorphism mediated Osimertinib resistance in egfr mutant lung cancer
Clinical Cancer Research, 2017Co-Authors: Azusa Tanimoto, Tadaaki Yamada, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Xavier Roca, Seiji YanoAbstract:Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non–small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against Osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism. Experimental Design: We used EGFR -mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of Osimertinib in vitro and in vivo . Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR. Results: EGFR -mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to Osimertinib in a polymorphism dosage–dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion–positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in Osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with Osimertinib could regress tumors in EGFR -mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR -T790M mutations. Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with Osimertinib, for treating EGFR -mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139–49. ©2016 AACR .
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histone deacetylase 3 inhibition overcomes bim deletion polymorphism mediated Osimertinib resistance in egfr mutant lung cancer
Clinical Cancer Research, 2017Co-Authors: Azusa Tanimoto, Tadaaki Yamada, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Xavier Roca, Tiong S Ong, Seiji YanoAbstract:Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non-small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against Osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism.Experimental Design: We used EGFR-mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of Osimertinib in vitro and in vivo Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR.Results:EGFR-mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to Osimertinib in a polymorphism dosage-dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion-positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in Osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with Osimertinib could regress tumors in EGFR-mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR-T790M mutations.Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with Osimertinib, for treating EGFR-mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139-49. ©2016 AACR.
