Related Experiment Video

Updated: Feb 19, 2026

Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
07:59

Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer

Published on: September 8, 2023

1.8K

Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers

Collin M Blakely1,2, Thomas B K Watkins3, Wei Wu1,2

  • 1Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

Nature Genetics
|November 7, 2017
PubMed

Insights

Targeting single genes in cancer (like EGFR in lung cancer) faces resistance. This study found co-occurring genetic changes (like WNT/β-catenin and cell-cycle genes) that limit treatment effectiveness and drive metastasis in advanced lung cancer.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Targeted therapies, such as EGFR inhibitors, are a cornerstone of modern cancer treatment.
  • Genetic resistance to these therapies significantly limits patient survival and treatment efficacy.
  • Understanding the genomic landscape of advanced lung cancer is crucial for overcoming resistance.

Purpose of the Study:

  • To identify co-occurring oncogenic events in advanced-stage EGFR-mutant lung cancer.
  • To define novel pathways that contribute to EGFR-inhibitor resistance.
  • To investigate the functional impact of co-occurring genetic alterations on tumor progression and treatment response.

Main Methods:

  • Genomic analysis of 1,122 cell-free DNA samples from EGFR-mutant lung cancer patients.
  • Whole-exome sequencing of seven longitudinally collected tumor samples from a patient.
  • Analysis of co-occurring alterations in WNT/β-catenin pathway genes and cell-cycle genes (CDK4, CDK6).

Main Results:

  • Identified critical co-occurring oncogenic events in most advanced-stage EGFR-mutant lung cancers.
  • Defined new pathways limiting EGFR-inhibitor response, including WNT/β-catenin alterations and CDK4/CDK6 mutations.
  • Observed increased tumor genomic complexity with EGFR-inhibitor treatment.
  • CTNNB1 and PIK3CA co-alterations showed nonredundant functions promoting metastasis or limiting EGFR-inhibitor response.

Conclusions:

  • Revisiting the single-driver oncogene paradigm is necessary for understanding advanced lung cancer.
  • Co-occurring genetic alterations play a critical role in treatment resistance and clinical outcomes.
  • These findings provide insights into novel therapeutic strategies for EGFR-mutant lung cancer.

More Related Videos

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure09:38

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Published on: August 11, 2017

9.2K
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors11:15

Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors

Published on: September 20, 2016

25.1K

Related Concept Videos

Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
8.2K
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
24
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
Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
7.2K
Cancer-Critical Genes I: Proto-oncogenes01:33

Cancer-Critical Genes I: Proto-oncogenes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
11.5K
Tumor Progression02:07

Tumor Progression

Tumor progression is a phenomenon where the pre-formed tumor acquires successive mutations to become clinically more aggressive and malignant. In the 1950s, Foulds first described the stepwise progression of cancer cells through successive stages.
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
7.5K