A systematic review and meta-analysis of individual patient data on the impact of the BIM deletion polymorphism on treatment outcomes in epidermal growth factor receptor mutant lung cancer

Soh, Sheila; Siddiqui, Fahad Javaid; Allen, John C.; Kim, Go Woon; Lee, Jae Cheol; Yatabe, Yasushi; Soda, Manabu; Mano, Hiroyuki; Soo, Ross A.; Chin, Tan Min; Ebi, Hiromichi; Yano, Seiji; Matsuo, Keitaro; Niu, Xiaomin; Lü, Shun; Isobe, Kazutoshi; Lee, Jih Hsiang; Yang, James Chih‐Hsin; Zhao, Ming; Zhou, Caicun; Lee, Jake June-Koo; Lee, Se‐Hoon; Lee, Ji Yun; Ahn, Myung Ju; Tan, Tira Jing Ying; Tan, Daniel Shao-Weng; Tan, Eng Huat; Ong, S. Tiong; Lim, Darren Wan-Teck

doi:10.18632/oncotarget.17102

Cited by 15 publications

(11 citation statements)

References 54 publications

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“…The NCC Oncopanel test also detected an Asian‐specific polymorphism in BCL2L11/BIM , which is thought to be associated with resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors . The deletion allele conferring resistance was observed in 24 (12.8%) cases, which is consistent with the percentage in the Asian population …”

Section: Resultssupporting

confidence: 63%

“…27 The deletion allele conferring resistance was observed in 24 (12.8%) cases, which is consistent with the percentage in the Asian population. 28 According to evidence levels 1A-3A, 109 cases (58.2%) harbored at least 1 actionable gene aberration (Figure 2A) Next, we examined the percentage of cases with each tumor type ( Figure 2B). When the 187 cases were categorized as carcinoma…”

Section: Percentage Of Cases Harboring Actionable Gene Aberrationsmentioning

confidence: 99%

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Feasibility and utility of a panel testing for 114 cancer‐associated genes in a clinical setting: A hospital‐based study

Ichikawa²,

et al. 2019

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Next‐generation sequencing ( NGS ) of tumor tissue (ie, clinical sequencing) can guide clinical management by providing information about actionable gene aberrations that have diagnostic and therapeutic significance. Here, we undertook a hospital‐based prospective study ( TOP ‐ GEAR project, 2nd stage) to investigate the feasibility and utility of NGS ‐based analysis of 114 cancer‐associated genes (the NCC Oncopanel test). We examined 230 cases (comprising more than 30 tumor types) of advanced solid tumors, all of which were matched with nontumor samples. Gene profiling data were obtained for 187 cases (81.3%), 111 (59.4%) of which harbored actionable gene aberrations according to the Clinical Practice Guidelines for Next Generation Sequencing in Cancer Diagnosis and Treatment (Edition 1.0) issued by 3 major Japanese cancer‐related societies. Twenty‐five (13.3%) cases have since received molecular‐targeted therapy according to their gene aberrations. These results indicate the utility of tumor‐profiling multiplex gene panel testing in a clinical setting in Japan. This study is registered with UMIN Clinical Trials Registry ( UMIN 000011141).

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Section: Resultssupporting

confidence: 63%

Section: Percentage Of Cases Harboring Actionable Gene Aberrationsmentioning

confidence: 99%

Feasibility and utility of a panel testing for 114 cancer‐associated genes in a clinical setting: A hospital‐based study

Ichikawa²,

et al. 2019

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“…While the presence of the BIM deletion reduces the first-line response to imatinib in CML patients [ 19 ], in EGFR-NSCLC patients it predicts an inferior OS compared to individuals without the deletion (28.8 vs 40.2 months respectively, p<0.017) [ 20 ]. Four independent groups from Taiwan, China, and Japan have replicated our findings [ 21 – 25 ], although two South Korean centres did not show any differences [ 26 , 27 ], which may possibly be due to genetic differences between East Asians [ 28 , 29 ].…”

Section: Introductionsupporting

confidence: 68%

Overcoming imatinib resistance conferred by the BIM deletion polymorphism in chronic myeloid leukemia with splice-switching antisense oligonucleotides

Bhadra

Sinnakannu

et al. 2017

Oncotarget

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Many tyrosine kinase-driven cancers, including chronic myeloid leukemia (CML), are characterized by high response rates to specific tyrosine kinase inhibitors (TKIs) like imatinib. In East Asians, primary imatinib resistance is caused by a deletion polymorphism in Intron 2 of the BIM gene, whose product is required for TKI-induced apoptosis. The deletion biases BIM splicing from exon 4 to exon 3, generating splice isoforms lacking the exon 4-encoded pro-apoptotic BH3 domain, which impairs the ability of TKIs to induce apoptosis. We sought to identify splice-switching antisense oligonucleotides (ASOs) that block exon 3 but enhance exon 4 splicing, and thereby resensitize BIM deletion-containing cancers to imatinib. First, we mapped multiple cis-acting splicing elements around BIM exon 3 by minigene mutations, and found an exonic splicing enhancer acting via SRSF1. Second, by a systematic ASO walk, we isolated ASOs that corrected the aberrant BIM splicing. Eight of 67 ASOs increased exon 4 levels in BIM deletion-containing cells, and restored imatinib-induced apoptosis and TKI sensitivity. This proof-of-principle study proves that resistant CML cells by BIM deletion polymorphism can be resensitized to imatinib via splice-switching BIM ASOs. Future optimizations might yield a therapeutic ASO as precision-medicine adjuvant treatment for BIM-polymorphism-associated TKI-resistant CML and other cancers.

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“…Others have previously demonstrated that BIM expression is required for response to EGFR TKIs (35, 37–39). Additionally, BIM polymorphisms which result in decreased expression of functional BIM protein, are associated with resistance to EGFR TKIs (32, 54, 55). Here, we establish that TWIST1 suppresses BIM expression through direct binding at both the promoter and intronic regions.…”

Section: Discussionmentioning

confidence: 99%

Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer

et al. 2018

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Patients with EGFR-mutant non-small-cell lung cancer (NSCLC) have significantly benefited from the use of EGFR tyrosine kinase inhibitors (TKIs). However, long-term efficacy of these therapies is limited due to de novo resistance (~30%) as well as acquired resistance. Epithelial-mesenchymal transition transcription factors (EMT-TFs), have been identified as drivers of EMT-mediated resistance to EGFR TKIs, however, strategies to target EMT-TFs are lacking. As the third generation EGFR TKI, osimertinib, has now been adopted in the first-line setting, the frequency of T790M mutations will significantly decrease in the acquired resistance setting. Previously less common mechanisms of acquired resistance to first generation EGFR TKIs including EMT are now being observed at an increased frequency after osimertinib. Importantly, there are no other FDA approved targeted therapies after progression on osimertinib. Here, we investigated a novel strategy to overcome EGFR TKI resistance through targeting the EMT-TF, TWIST1, in EGFR-mutant NSCLC. We demonstrated that genetic silencing of TWIST1 or treatment with the TWIST1 inhibitor, harmine, resulted in growth inhibition and apoptosis in EGFR-mutant NSCLC. TWIST1 overexpression resulted in erlotinib and osimertinib resistance in EGFR-mutant NSCLC cells. Conversely, genetic and pharmacological inhibition of TWIST1 in EGFR TKI-resistant EGFR-mutant cells increased sensitivity to EGFR TKIs. TWIST1-mediated EGFR TKI resistance was due in part to TWIST1 suppression of transcription of the pro-apoptotic BH3-only gene, BCL2L11 (BIM), by directly binding to BCL2L11 intronic regions and promoter. As such, pan-BCL2 inhibitor treatment overcame TWIST1-mediated EGFR TKI resistance and were more effective in the setting of TWIST1 overexpression. Finally, in a mouse model of autochthonous EGFR-mutant lung cancer, Twist1 overexpression resulted in erlotinib resistance and suppression of erlotinib-induced apoptosis. These studies establish TWIST1 as a driver of resistance to EGFR TKIs and provide rationale for use of TWIST1 inhibitors or BCL2 inhibitors as means to overcome EMT-mediated resistance to EGFR TKIs.

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A systematic review and meta-analysis of individual patient data on the impact of the BIM deletion polymorphism on treatment outcomes in epidermal growth factor receptor mutant lung cancer

Cited by 15 publications

References 54 publications

Feasibility and utility of a panel testing for 114 cancer‐associated genes in a clinical setting: A hospital‐based study

Feasibility and utility of a panel testing for 114 cancer‐associated genes in a clinical setting: A hospital‐based study

Overcoming imatinib resistance conferred by the BIM deletion polymorphism in chronic myeloid leukemia with splice-switching antisense oligonucleotides

Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer

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