Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study

Lee, J. K.; Shin, Jong Yeon; Kim, S.; Lee, S.; Park, C.; Kim, Ju Yeong; Koh, Youngil; Keam, Bhumsuk; Min, Hye Sook; Kim, T. M.; Jeon, Yoon Kyung; Kim, Dong-Wan; Chung, Doo Hyun; Heo, Dae Seog; Lee, S. H.; Kim, Jong‐Il

doi:10.1093/annonc/mdt127

Cited by 104 publications

(100 citation statements)

References 41 publications

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“…Several techniques have been used to detect the T790M mutation in pretreatment EGFR-mutant lung cancer samples with varying results. The mutation was detected in 2% to 3% of samples by Sanger sequencing (7,26), in 4% by a mutantenriched PCR assay (7), in 9% by targeted deep sequencing (27), in 31.5% by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (15), and in 79% by colony hybridization (ref. 18; Supplementary Table S7).…”

Section: Discussionmentioning

confidence: 99%

The Impact of EGFR T790M Mutations and BIM mRNA Expression on Outcome in Patients with EGFR-Mutant NSCLC Treated with Erlotinib or Chemotherapy in the Randomized Phase III EURTAC Trial

Costa

Molina

Drozdowskyj

et al. 2014

Clinical Cancer Research

208

200

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Purpose: Concomitant genetic alterations could account for transient clinical responses to tyrosine kinase inhibitors of the EGF receptor (EGFR) in patients harboring activating EGFR mutations.Experimental Design: We have evaluated the impact of pretreatment somatic EGFR T790M mutations, TP53 mutations, and Bcl-2 interacting mediator of cell death (BCL2L11, also known as BIM) mRNA expression in 95 patients with EGFR-mutant non-small-cell lung cancer (NSCLC) included in the EURTAC trial (trial registration: NCT00446225).Results: T790M mutations were detected in 65.26% of patients using our highly sensitive method based on laser microdissection and peptide-nucleic acid-clamping PCR, which can detect the mutation at an allelic dilution of 1 in 5,000. Progression-free survival (PFS) to erlotinib was 9.7 months for those with T790M mutations and 15.8 months for those without, whereas among patients receiving chemotherapy, it was 6 and 5.1 months, respectively (P < 0.0001). PFS to erlotinib was 12.9 months for those with high and 7.2 months for those with low/intermediate BCL2L11 expression levels, whereas among chemotherapy-treated patients, it was 5.8 and 5.5 months, respectively (P ¼ 0.0003). Overall survival was 28.6 months for patients with high BCL2L11 expression and 22.1 months for those with low/intermediate BCL2L11 expression (P ¼ 0.0364). Multivariate analyses showed that erlotinib was a marker of longer PFS (HR ¼ 0.35; P ¼ 0.0003), whereas high BCL2L11 expression was a marker of longer PFS (HR ¼ 0.49; P ¼ 0.0122) and overall survival (HR ¼ 0.53; P ¼ 0.0323).Conclusions: Low-level pretreatment T790M mutations can frequently be detected and can be used for customizing treatment with T790M-specific inhibitors. BCL2L11 mRNA expression is a biomarker of survival in EGFR-mutant NSCLC and can potentially be used for synthetic lethality therapies.

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Section: Discussionmentioning

confidence: 99%

The Impact of EGFR T790M Mutations and BIM mRNA Expression on Outcome in Patients with EGFR-Mutant NSCLC Treated with Erlotinib or Chemotherapy in the Randomized Phase III EURTAC Trial

Costa

Molina

Drozdowskyj

et al. 2014

Clinical Cancer Research

208

200

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“…The presence of T790M-resistant mutations or other rare exon 20 mutations has been described in only a very small percentage of patients before exposure to EGFR-TKI treatment (19). Several studies showed that many EGFR-mutated NSCLC patients carry a common germline polymorphism of the proapoptotic gene BIM that results in deletion of the death-inducing BH3 domain of BIM and intrinsic resistance to EGFR-TKI therapy (20,21), although the finding could not be confirmed in another study (22). Moreover, BIM expression is a good marker in predicting TKI resistance (23,24).…”

Section: Introductionmentioning

confidence: 98%

CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance

Park¹,

Raffeld²,

Moon³

et al. 2014

J. Clin. Invest.

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“…Indeed, decreased protein levels of EGFR and activity of ERK1/2 were detected in ERb1-expressing NSCLC cells. These results together with the upregulation of the proapoptotic marker BIM that predicts response to EGFR-TKI treatment and is degraded in response to ERK1/2 activation strengthened the inhibition of the EGFR-RAS pathway by ERb1 in NSCLC cells (38,39,48).…”

Section: Discussionmentioning

confidence: 79%

ERβ Regulates NSCLC Phenotypes by Controlling Oncogenic RAS Signaling

Nikolos

Thomas

Rajapaksa

et al. 2014

Molecular Cancer Research

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Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. In addition to the aberrant growth factor signaling, dysregulation of other pathways, such as those mediated by estrogens and their receptors, has been linked to NSCLC initiation and progression. Although the expression of wild-type estrogen receptor b (ERb1) has been associated with prolonged disease-free survival in patients with NSCLC, the molecular mechanism that accounts for this correlation is unknown. Here, upregulation of ERb1 reduced proliferation and enhanced apoptosis in the context of mutant RAS. ERb1 was found to induce apoptosis by stimulating the intrinsic apoptotic pathway that involves BIM, a Bcl-2 proapoptotic family member that is regulated by the extracellular signal-regulated kinase (ERK). Downregulation of EGFR and inactivation of RAS and the downstream components ERK1/2 were found to be involved in the ERb1-induced apoptosis. Manipulation of EGFR and RAS expression and activity in ERb1-expressing cells revealed the central role of oncogenic RAS inhibition in the ERb1-mediated proapoptotic phenotype and EGFR regulation. These results demonstrate that ERb1 decreases the survival of NSCLC cells by regulating oncogenic RAS signaling.

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Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study

Abstract: We identified coexistent genetic alterations of cancer-related genes that could explain primary resistance in a small proportion of patients. Our result suggests that the mechanism of primary resistance might be heterogeneous.

Cited by 104 publications

References 41 publications

The Impact of EGFR T790M Mutations and BIM mRNA Expression on Outcome in Patients with EGFR-Mutant NSCLC Treated with Erlotinib or Chemotherapy in the Randomized Phase III EURTAC Trial

The Impact of EGFR T790M Mutations and BIM mRNA Expression on Outcome in Patients with EGFR-Mutant NSCLC Treated with Erlotinib or Chemotherapy in the Randomized Phase III EURTAC Trial

CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance

ERβ Regulates NSCLC Phenotypes by Controlling Oncogenic RAS Signaling

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