The <i>BIM</i> deletion polymorphism: A paradigm of a permissive interaction between germline and acquired TKI resistance factors in chronic myeloid leukemia

Ko, Tun Kiat; Chin, Hui San; Chuah, Charles; Huang, John; Ng, King-Pan; Khaw, Seong Lin; Huang, David C.S.; Ong, S. Tiong

doi:10.18632/oncotarget.5436

Cited by 16 publications

(6 citation statements)

References 33 publications

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“…One possible strategy to overcome the resistance and restore the response to TKIs is adding BH3-mimetic drug or histone deacetylase (HDAC) inhibition. In vitro experiments revealed that the addition of BH3-mimetic drug ABT-737 with imatinib enhanced the TKI-induced apoptosis and cell death in deletion-containing cells [ 18 , 47 ]. The other studies demonstrated that the HDAC inhibitor vorinostat could circumvent TKI resistance in EGFR-mutant NSCLC cell lines harboring BIM deletion polymorphism [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of BIM Deletion in EGFR‐Mutant NSCLC Patients Treated with EGFR‐TKIs: A Meta‐Analysis

Lv¹,

Sun²,

Yang³

et al. 2021

BioMed Research International

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Background. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is inevitable in EGFR-mutant non-small-cell lung cancer (NSCLC) patients. A germline 2903 bp deletion polymorphism of Bcl-2-like protein 11 (BIM) causes reduced expression of proapoptotic BH3-only BIM protein and blocks TKI-induced apoptosis of tumor cells. Yet the association between the deletion polymorphism and response to EGFR-TKI treatment remains inconsistent among clinical observations. Thus, we performed the present meta-analysis. Methods. Eligible studies were identified by searching PubMed, Embase, and ClinicalTrials.gov databases prior to March 31, 2021. Hazard ratios (HRs) and 95% confidence intervals (CIs) of progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) and 95% CIs of objective response rate (ORR) and disease control rate (DCR) were calculated by using a random effects model. Sensitivity, metaregression, and publication bias analyses were also performed. Results. A total of 20 datasets (3003 EGFR-mutant NSCLC patients receiving EGFR-TKIs from 18 studies) were included. There were 475 (15.8%) patients having the 2903-bp intron deletion of BIM and 2528 (84.2%) wild-type patients. BIM deletion predicted significantly shorter PFS ( HR = 1.35 , 95% CI: 1.10-1.64, P = 0.003 ) and a tendency toward an unfavorable OS ( HR = 1.22 , 95% CI: 0.99-1.50, P = 0.068 ). Patients with deletion polymorphism had lower ORR ( OR = 0.60 , 95% CI: 0.42-0.85, P = 0.004 ) and DCR ( OR = 0.59 , 95% CI: 0.38-0.90, P = 0.014 ) compared with those without deletion. Conclusion. BIM deletion polymorphism may confer resistance to EGFR-TKIs and can be used as a biomarker to predict treatment response to EGFR-TKIs in EGFR-mutant NSCLC patients from Asian populations.

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Section: Discussionmentioning

confidence: 99%

Prognostic Value of BIM Deletion in EGFR‐Mutant NSCLC Patients Treated with EGFR‐TKIs: A Meta‐Analysis

Lv¹,

Sun²,

Yang³

et al. 2021

BioMed Research International

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“…The most common polymorphism in BIM is present in ≈21% of the East Asian population and results in an alternatively spliced mRNA, lacking the BH3 proapoptotic domain. 24,39 This mutation seems to cause resistance to treatment in different types of lung cancer, 39 but its effect of imatinib resistance in the clinic is still questioned. 24 For such resistant patients, navitoclax and imatinib combined could have more beneficial effects.…”

Section: Discussionmentioning

confidence: 99%

A genome‐scale CRISPR knock‐out screen in chronic myeloid leukemia identifies novel drug resistance mechanisms along with intrinsic apoptosis and MAPK signaling

et al. 2020

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Understanding resistance mechanisms in cancer is of utmost importance for the discovery of novel “druggable” targets. Efficient genetic screening, now even more possible with CRISPR‐Cas9 gene‐editing technology, next‐generation sequencing and bioinformatics, is an important tool for deciphering novel cellular processes, such as resistance to treatment in cancer. Imatinib specifically eliminates chronic myeloid leukemia (CML) cells by targeting and blocking the kinase activity of BCR‐ABL1; however, resistance to treatment exists. In order to discover BCR‐ABL1 independent mechanisms of imatinib resistance, we utilized the genome‐scale CRISPR knock‐out library to screen for imatinib‐sensitizing genes in vitro on K562 cells. We revealed genes that seem essential for imatinib‐induced cell death, such as proapoptotic genes (BIM, BAX) or MAPK inhibitor SPRED2. Specifically, reestablishing apoptosis in BIM knock‐out (KO) cells with BH3 mimetics, or inhibiting MAPK signaling in SPRED2 KO cells with MEK inhibitors restores sensitivity to imatinib. In this work, we discovered previously identified pathways and novel pathways that modulate response to imatinib in CML cell lines, such as the implication of the Mediator complex, mRNA processing and protein ubiquitinylation. Targeting these specific genetic lesions with combinational therapy can overcome resistance phenotypes and paves the road for the use of precision oncology.

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“…Exon 4 of BIM encodes a BH3 domain, which is essential for the pro-apoptotic function of BIM. The exon 4-to-exon 3 switch introduces a polyadenylation signal sequence leading to premature translation termination and loss of the BH3 domain [ 129 , 130 ]. Indeed, BCR-ABL-positive CML and EGFR mutation-positive non-small cell lung cancer (NSCLC) cells expressing BIM-γ exhibit resistance to imatinib and gefitinib (EGFR TKI), respectively [ 124 ].…”

Section: Aberrant Mrna Splicing and Cancer Drug Resistancementioning

confidence: 99%

Aberrant RNA Splicing in Cancer and Drug Resistance

Wang

Lee

2018

Cancers

141

115

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More than 95% of the 20,000 to 25,000 transcribed human genes undergo alternative RNA splicing, which increases the diversity of the proteome. Isoforms derived from the same gene can have distinct and, in some cases, opposing functions. Accumulating evidence suggests that aberrant RNA splicing is a common and driving event in cancer development and progression. Moreover, aberrant splicing events conferring drug/therapy resistance in cancer is far more common than previously envisioned. In this review, aberrant splicing events in cancer-associated genes, namely BCL2L1, FAS, HRAS, CD44, Cyclin D1, CASP2, TMPRSS2-ERG, FGFR2, VEGF, AR and KLF6, will be discussed. Also highlighted are the functional consequences of aberrant splice variants (BCR-Abl35INS, BIM-γ, IK6, p61 BRAF V600E, CD19-∆2, AR-V7 and PIK3CD-S) in promoting resistance to cancer targeted therapy or immunotherapy. To overcome drug resistance, we discuss opportunities for developing novel strategies to specifically target the aberrant splice variants or splicing machinery that generates the splice variants. Therapeutic approaches include the development of splice variant-specific siRNAs, splice switching antisense oligonucleotides, and small molecule inhibitors targeting splicing factors, splicing factor kinases or the aberrant oncogenic protein isoforms.

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The BIM deletion polymorphism: A paradigm of a permissive interaction between germline and acquired TKI resistance factors in chronic myeloid leukemia

Cited by 16 publications

References 33 publications

Prognostic Value of BIM Deletion in EGFR‐Mutant NSCLC Patients Treated with EGFR‐TKIs: A Meta‐Analysis

Prognostic Value of BIM Deletion in EGFR‐Mutant NSCLC Patients Treated with EGFR‐TKIs: A Meta‐Analysis

A genome‐scale CRISPR knock‐out screen in chronic myeloid leukemia identifies novel drug resistance mechanisms along with intrinsic apoptosis and MAPK signaling

Aberrant RNA Splicing in Cancer and Drug Resistance

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