Evidence map›Paper›PMID 26992917›Full record

ArticleNeoplasia (New York, N.Y.)2016

Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non-Small Cell Lung Cancer Cells.

Xuyuan Dong, Ester Fernandez-Salas, Enxiao Li, Shaomeng Wang

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neoplasia (New York, N.Y.), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.

0numbers the graph read from it
0cells of the map it votes in
37citing papers in PubMed
8.5field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

37 citing papers in PubMed, 69 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

4 authors at 2 institutions in 2 countries.

Xuyuan DongDepartment of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China; University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
Ester Fernandez-SalasUniversity of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
Enxiao LiDepartment of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China. Electronic address: doclienxiao@sina.com.
Shaomeng WangUniversity of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, 48109, USA. Electronic address: shaomeng@umich.edu.
First Affiliated Hospital of Xi'an Jiaotong University · CNUniversity of Michigan–Ann Arbor · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non-small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines. Rather, overexpression of phospho-ALK and alternative receptor tyrosine kinases such as phospho-EGFR, phospho-HER3, and phospho-IGFR-1R was observed in both resistant cell lines. Additionally, NRG1, a ligand for HER3, is upregulated and responsible for resistance by activating the EGFR family pathways through the NRG1-HER3-EGFR axis. Combination treatment with EGFR inhibitors, in particular afatinib, was shown to be effective at overcoming resistance. Our study provides new mechanistic insights into adaptive resistance to second-generation ALK inhibitors and suggests a potential clinical strategy to combat resistance to these second-generation ALK inhibitors in NSCLC.

Indexed as

Anaplastic Lymphoma KinaseCarbazolesCarcinoma, Non-Small-Cell LungCell Line, TumorDrug Resistance, NeoplasmErbB ReceptorsGene Expression Regulation, NeoplasticGlial Cell Line-Derived Neurotrophic Factor ReceptorsHumansMutationNeuregulin-1Oncogene Proteins, FusionPiperidinesPyrimidinesReceptor, ErbB-3Receptor Protein-Tyrosine KinasesalectinibALK protein, humanAnaplastic Lymphoma KinaseCarbazolesceritinibEGFR protein, humanEML4-ALK fusion protein, humanERBB3 protein, humanErbB ReceptorsGFRA1 protein, humanGlial Cell Line-Derived Neurotrophic Factor ReceptorsNeuregulin-1NRG1 protein, humanOncogene Proteins, FusionPiperidinesPyrimidinesReceptor, ErbB-3Receptor Protein-Tyrosine KinasesSulfones

Identifiers

PMID26992917
PMCPMC4796802
OpenAlexW2299266038

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.