Mimicking the BIM BH3 domain overcomes resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer

Xia, Jinjing; Bai, Hao; Yan, Bo; Li, Rong; Shao, Minhua; Xiong, Liwen; Han, Baohui

doi:10.18632/oncotarget.19411

Cited by 15 publications

(16 citation statements)

References 31 publications

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“…On the other hand, the decreased expression of EGFR and increased expression of p-Akt were observed in H1975AR compare to H1975, which was consistent with the resistant mechanisms of another previously established AZD9291-resistant H1975 (Tang et al 2016). Lung cancer with decreased EGFR expression was reported to be sensitive to the BIM BH3 mimetic drug, navitoclax (ABT-263) (Niederst et al 2015;Xia et al 2017), and the upregulated BIM, as a proapoptotic member of Bcl-2 family, was required for apoptosis induced by EGFR-TKIs (Huang and Fu 2015;Xia et al 2017). ABT-263 was also reported to be effective in overcoming the acquired resistance of AZD9291 in AZD9291-resistant H1975 by inhibition of Bcl2 and activation of caspase (Tang et al 2016).…”

Section: Discussionsupporting

confidence: 72%

Overcoming acquired resistance of gefitinib in lung cancer cells without T790M by AZD9291 or Twist1 knockdown in vitro and in vivo

Liu

Gao

2019

Arch Toxicol

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The T790M mutation is recognized as a typical mechanism of acquired resistance to first generation of epithermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib in non-small cell lung cancer (NSCLC) patients who are commonly treated by third generation of EGFR-TKI AZD9291 (osimertinib). However, the therapeutic strategy for overcoming acquired resistance to EGFR-TKIs in NSCLC patients without T790M remains to be definitively determined. In the present study, gefitinib-resistant H1650 (H1650GR) or AZD9291 resistant H1975 (H1975AR) was generated by exposing NSCLC cell line H1650 or H1975 to progressively increased concentrations of gefitinib or AZD9291 over 11 months. The cytotoxic effects of gefitinib or AZD9291 in vitro were evaluated via the half maximal inhibitory concentrations (IC50s) determined by the MTT assay. IC50 of gefitinib in H1650GR (50.0±3.0 μM) significantly increased compared with H1650 (31.0±1.0 μM) (p<0.05). Similarly, the IC50 of AZD9291 in H1975AR (10.3± 0.9 μM) significantly increased compared with H1975 (5.5±0.6 μM) (p<0.05). However, IC50 of AZD9291 on H1650GR (8.5 ± 0.5 μM) did not increase compared with H1650 (9.7 ± 0.7 μM). On the other hand, IC50 of AZD9291 on gefitinib-resistant A549 (A549GR established in our previous study) (12.7 ± 0.8 μM) was significantly increased compared with A549 (7.0 ± 1.0 μM) (p<0.05). AZD9291 induced caspase 3/7 activation in A549, H1650, and H1650GR, but not in A549GR. Western blot analyses showed that p-Akt played a key role in determining the sensitivities of A549, A549GR, H1650, and H1650GR to gefitinib or AZD9291. Additionally, increased expression of Twist1 was observed in all cells with acquired EGFR-TKI resistance and knockdown of Twist1 by shRNA was found to significantly enhance the sensitivity of A549GR to gefitinib or AZD9291 via reversing epithelial mesenchymal transition (EMT) and downregulating p-Akt, but not of H1975AR to AZD9291. The enhanced cytotoxic

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Section: Discussionsupporting

confidence: 72%

Overcoming acquired resistance of gefitinib in lung cancer cells without T790M by AZD9291 or Twist1 knockdown in vitro and in vivo

Liu

Gao

2019

Arch Toxicol

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“…Consequently, this polymorphism impairs the generation of the proapoptotic isoform of BIM required for EGFR-TKI-induced apoptosis and confers an intrinsically TKI-resistant phenotype that can partly explain the heterogeneity of TKI responses across individuals [220]. Indeed, Asian patients with EGFR M+ NSCLC, who harbored this host BIM deletion polymorphism, exhibited significantly inferior responses to treatment with TKIs of all three generations and much shorter PFS than individuals lacking the polymorphism, suggesting that the BIM polymorphism is a negative predictive marker of response to EGFR-TKIs [218,219,220,221,222]. Of note, preclinical experiments indicate that BH3-mimetics or HDAC-inhibitors, such as vorinostat, can restore BIM functionality and sensitivity to EGFR-TKIs in EGFR M+ NSCLC cells carrying the BIM polymorphism [221,222,223].…”

Section: Clinical and Preclinical Studies Shedding Light On Intrinmentioning

confidence: 99%

“…Indeed, Asian patients with EGFR M+ NSCLC, who harbored this host BIM deletion polymorphism, exhibited significantly inferior responses to treatment with TKIs of all three generations and much shorter PFS than individuals lacking the polymorphism, suggesting that the BIM polymorphism is a negative predictive marker of response to EGFR-TKIs [218,219,220,221,222]. Of note, preclinical experiments indicate that BH3-mimetics or HDAC-inhibitors, such as vorinostat, can restore BIM functionality and sensitivity to EGFR-TKIs in EGFR M+ NSCLC cells carrying the BIM polymorphism [221,222,223]. In addition to polymorphism, low BIM expression levels in EGFR M+ NSCLC samples may also predict poorer initial response and shorter duration of clinical benefit from EGFR-TKIs [57,212,224,225].…”

Section: Clinical and Preclinical Studies Shedding Light On Intrinmentioning

confidence: 99%

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

Santoni-Rugiu

Melchior

Urbanska

et al. 2019

Cancers

125

126

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Activating mutations in the epidermal growth factor receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated (EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20–30% of patients do not respond or respond for a very short time (<3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined by analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent in EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them.

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“…For two studies, each reported two unrelated cohorts [21,23]. Finally, 20 datasets from 18 studies [18][19][20][21][22][23][35][36][37][38][39][40][41][42][43][44][45][46] exploring the association between BIM deletion polymorphism and EGFR-TKI efficacy in EGFR-mutant NSCLC patients were included in our meta-analysis (Figure 1).…”

Section: Characteristics Of Eligible Studiesmentioning

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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Mimicking the BIM BH3 domain overcomes resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer

Cited by 15 publications

References 31 publications

Overcoming acquired resistance of gefitinib in lung cancer cells without T790M by AZD9291 or Twist1 knockdown in vitro and in vivo

Overcoming acquired resistance of gefitinib in lung cancer cells without T790M by AZD9291 or Twist1 knockdown in vitro and in vivo

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

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

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