BIM deletion polymorphisms in Hispanic patients with non-small cell lung cancer carriers of EGFR mutations

Cardona, Andrés F.; Rojas, Leonardo; Wills, Beatriz; Arrieta, Óscar; Carranza, Hernán; Vargas, Carlos; Otero, Jorge; Corrales-Rodriguez, Luis; Martín, Claudio; Reguart, Noemı́; Archila, Pilar; Rodríguez, July; Cuello, M.; Ortíz, Carlos; Franco, Sandra; Rolfo, Christian; Rosell, Rafael

doi:10.18632/oncotarget.12112

Cited by 30 publications

(29 citation statements)

References 36 publications

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“…In contrast, Bim downregulation following siRNA transfection delayed paclitaxel-induced apoptosis, suggesting that low expression of Bim is responsible for paclitaxel-resistance in cancer cells (52). It has also been demonstrated that Bim deletion polymorphisms are associated with a poor clinical response to erlotinib and may be an independent prognostic factor for patients with non-small cell lung cancer with the EGFR mutation (53,54). Collectively, these previous studies suggest that many chemotherapeutic agents use Bim to trigger apoptosis in a variety of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Cdc20 inhibitor apcin inhibits the growth and invasion of osteosarcoma cells

et al. 2018

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Osteosarcoma (OS) is the most common primary malignant bone tumor worldwide, primarily affecting children and adolescents. The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that is activated by its co‑activator Cdc20 during the metaphase‑anaphase transition. Apcin is a novel cell‑permeable molecule that blocks the interaction between APC/C and Cdc20. Cdc20 overexpression has been reported in various malignancies and plays an oncogenic role in tumorigenesis and tumor progression. In the present study, the antitumor properties of apcin, an inhibitor of Cdc20, was investigated in OS cell lines. In addition, the possible molecular target by which apcin mediates cell death was explored. Apcin was demonstrated to inhibit OS cell growth and induce significant apoptosis. The invasion and mobile abilities of OS cells were also markedly suppressed by apcin treatment. Furthermore, Bim and p21 were upregulated in OS cells following apcin treatment. The results of the present study indicated that apcin may have therapeutic potential as a treatment for OS and that Cdc20 may be a promising molecular target for chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Cdc20 inhibitor apcin inhibits the growth and invasion of osteosarcoma cells

et al. 2018

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“…In East Asians, but not Caucasians or Africans, a 2,903-bp deletion polymorphism in the BIM gene was found to be present at incidences of around 13% and 0.5% for heterozygous and homozygous carriers, respectively (10). Another study has recently reported that 15.7% of hispanic patients with NSCLC carried the deletion allele (11). Importantly, the BIM deletion polymorphism results in the preferential splicing of exon 3 over the BH3-encoding exon 4 in the BIM pre-mRNA, and leads to the production of inactive BIM isoforms lacking the BH3 domain.…”

Section: Introductionmentioning

confidence: 98%

Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism–Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer

Tanimoto

Takeuchi

Arai

et al. 2017

Clinical Cancer Research

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The 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 mutations. Here, we investigated whether the 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. We used -mutated NSCLC cell lines, which were either heterozygous or homozygous for the deletion polymorphism, to evaluate the effect of osimertinib and Protein expression was examined by Western blotting. Alternative splicing of mRNA was analyzed by RT-PCR.-mutated NSCLC cell lines with the 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 deletion-positive cells revealed that vorinostat affected the alternative splicing of 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-mutated NSCLC cells homozygous for the deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired-T790M mutations. These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treating -mutated lung cancers carrying the deletion polymorphism. .

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“…It has previously been demonstrated that Bim is essential for EGFR-TKI-induced killing of NScLc cells (14). A recent study further demonstrated that a common Bim deletion polymorphism contributes to poor responses among NScLc patients with EGFR-mutations treated with EGFR-TKIs (15). Patients with this polymorphism were shown to have a reduced median progression-free survival (mPFS; 6.6 vs. 11.9 months, respectively; P=0.003) (16).…”

Section: Introductionmentioning

confidence: 97%

Decreased human antigen�R expression confers resistance to�tyrosine kinase inhibitors in epidermal growth factor receptor-mutant lung cancer by inhibiting Bim expression

et al. 2018

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Primary resistance to epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs) is an obstacle for the treatment of non‑small cell lung cancer (NSCLC); however, the associated mechanisms are not well understood. Studies have reported that Bim expression levels may be associated with the efficacy of EGFR‑TKI treatment in NSCLC patients harboring EGFR mutations. Human antigen R (HuR) regulates the mRNA and protein expression of target genes, including certain B‑cell lymphoma 2 family members. The present study investigated whether HuR mediates resistance to EGFR‑TKIs via the regulation of Bim. The results demonstrated that decreased levels of HuR and Bim protein expression are associated with primary resistance to EGFR‑TKIs and reduced median progression‑free survival in NSCLC patients. In vitro assays also revealed that knockdown of HuR resulted in primary EGFR‑TKI resistance and reduced gefitinib‑induced apoptosis in HCC827 cells by decreasing Bim expression. Furthermore, elevated HuR expression restored gefitinib sensitivity and enhanced gefitinib‑induced apoptosis in H1650 cells by increasing Bim expression. In vivo, it was further demonstrated that overexpression of HuR was able to restore the gefitinib sensitivity of H1650 cells. Therefore, altered HuR/Bim expression is proposed to be a novel mechanism of EGFR‑TKI resistance in NSCLC.

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BIM deletion polymorphisms in Hispanic patients with non-small cell lung cancer carriers of EGFR mutations

Cited by 30 publications

References 36 publications

Cdc20 inhibitor apcin inhibits the growth and invasion of osteosarcoma cells

Cdc20 inhibitor apcin inhibits the growth and invasion of osteosarcoma cells

Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism–Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer

Decreased human antigen�R expression confers resistance to�tyrosine kinase inhibitors in epidermal growth factor receptor-mutant lung cancer by inhibiting Bim expression

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