Related Experiment Video

Updated: Feb 16, 2026

Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
05:17

Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing

Published on: October 10, 2025

430

Mutations in EMT-Related Genes in ALK Positive Crizotinib Resistant Non-Small Cell Lung Cancers

Jiacong Wei1,2, Anthonie J van der Wekken3, Ali Saber4

  • 1Department of Genetics, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands. weijiacong@126.com.

Cancers
|January 5, 2018
PubMed

Insights

Tumors treated with crizotinib for anaplastic lymphoma kinase-positive non-small-cell lung cancer can develop resistance. This study found that epithelial-mesenchymal transition pathways are associated with crizotinib resistance in non-small-cell lung cancer.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Crizotinib is a targeted therapy for anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC).
  • Tumor resistance to crizotinib is a significant clinical challenge, with resistance mechanisms not fully understood.
  • Identifying genetic mutations driving resistance is crucial for developing effective treatment strategies.

Purpose of the Study:

  • To identify gene mutations associated with acquired resistance to crizotinib in ALK-positive advanced non-squamous NSCLC.
  • To investigate the role of specific molecular pathways in the development of crizotinib resistance.

Main Methods:

  • Whole exome sequencing was performed on paired pre- and post-crizotinib tumor tissues from four ALK-positive NSCLC patients with progressive disease.
  • Somatic variants were identified and analyzed to detect mutations specific to crizotinib-resistant tumors.
  • Pathway enrichment analysis was conducted to identify biological processes associated with identified mutations.

Main Results:

  • One patient had an ALK-resistance associated mutation.
  • The other three patients exhibited 89 relevant somatic mutations in 74 genes specific to resistant tumors, with no ALK mutations.
  • Mutations were significantly enriched in pathways related to epithelial-mesenchymal transition (EMT), including proteoglycans in cancer, HIF-1 signaling, FoxO signaling, and ECM-receptor interaction.

Conclusions:

  • Acquired resistance to crizotinib in ALK-positive NSCLC can occur through mechanisms independent of ALK mutations.
  • Enrichment of mutations in EMT-related pathways suggests that loss of epithelial differentiation is a key mechanism of crizotinib resistance.
  • Further research into EMT pathways may reveal new therapeutic targets for overcoming crizotinib resistance in NSCLC.
Keywords:
ALKadenocarcinomacrizotinib resistancewhole exome sequencing

More Related Videos

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

15.3K
Radiosensitivity of Cancer Stem Cells in Lung Cancer Cell Lines09:45

Radiosensitivity of Cancer Stem Cells in Lung Cancer Cell Lines

Published on: August 21, 2019

7.5K

Related Concept Videos

Chromatin Position Affects Gene Expression02:35

Chromatin Position Affects Gene Expression

Chromatin is the massive complex of DNA and proteins packaged inside the nucleus. The complexity of chromatin folding and how it is packaged inside the nucleus greatly influences  access to genetic information. Generally, the nucleus' periphery is considered transcriptionally repressive, while the cell's interior is considered a transcriptionally active area. 
Topologically Associated Domains (TADs)
The 3-dimensional positioning of chromatin in the nucleus influences the...
25.0K
Mutation, Gene Flow, and Genetic Drift01:09

Mutation, Gene Flow, and Genetic Drift

In a population that is not at Hardy-Weinberg equilibrium, the frequency of alleles changes over time. Therefore, any deviations from the five conditions of Hardy-Weinberg equilibrium can alter the genetic variation of a given population. Conditions that change the genetic variability of a population include mutations, natural selection, non-random mating, gene flow, and genetic drift (small population size).
64.7K
Cancers Originate from Somatic Mutations in a Single Cell02:21

Cancers Originate from Somatic Mutations in a Single Cell

Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...
15.0K
Mutations01:39

Mutations

Overview
94.7K
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.8K
Viral Mutations00:36

Viral Mutations

A mutation is a change in the sequence of bases of DNA or RNA in a genome. Some mutations occur during replication of the genome due to errors made by the polymerase enzymes that replicate DNA or RNA. Unlike DNA polymerase, RNA polymerase is prone to errors because it is not capable of “proofreading” its work. Viruses with RNA-based genomes, like HIV, therefore accrue mutations faster than viruses with DNA-based genomes. Because mutation and recombination provide the raw material...
40.0K