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Updated: Feb 17, 2026
Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
Published on: July 5, 2019
Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung Cancer
Wei Wu1,2, Franziska Haderk3,4, Trever G Bivona5,6
1Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115, USA. wei.wu@ucsf.edu.
Abstract:
Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified in lung cancer at 3-7% frequency, thus representing an important subset of genetic lesions that drive oncogenesis in this disease. Despite the availability of multiple FDA-approved small molecule inhibitors targeting ALK fusion proteins, drug resistance to ALK kinase inhibitors is a common problem in clinic. Thus, there is an unmet need to deepen the current understanding of genomic characteristics of ALK rearrangements and to develop novel therapeutic strategies that can overcome ALK inhibitor resistance. In this review, we present the genomic landscape of ALK fusions in the context of co-occurring mutations with other cancer-related genes, pointing to the central role of genetic epistasis (gene-gene interactions) in ALK-driven advanced-stage lung cancer. We discuss the possibility of targeting druggable domains within ALK fusion partners in addition to available strategies inhibiting the ALK kinase domain directly. Finally, we examine the potential of targeting ALK fusion-specific neoantigens in combination with other treatments, a strategy that could open a new avenue for the improved treatment of ALK positive lung cancer patients.
Insights
Anaplastic lymphoma kinase (ALK) gene rearrangements drive lung cancer, but resistance to ALK inhibitors is common. Understanding ALK genomic landscapes and gene interactions can reveal new strategies to overcome resistance in patients.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Anaplastic lymphoma kinase (ALK) gene rearrangements occur in 3-7% of lung cancers, driving oncogenesis.
- FDA-approved ALK inhibitors exist, but drug resistance is a significant clinical challenge.
- There is a critical need to understand ALK genomic characteristics and develop novel therapies for resistant cases.
Purpose of the Study:
- To review the genomic landscape of ALK fusions in lung cancer.
- To explore gene-gene interactions (genetic epistasis) in ALK-driven lung cancer.
- To discuss novel therapeutic strategies beyond direct ALK kinase inhibition.
Main Methods:
- Review of existing literature on ALK gene rearrangements in lung cancer.
- Analysis of genomic data regarding co-occurring mutations with ALK fusions.
- Exploration of therapeutic targets within ALK fusion partners and neoantigens.
Main Results:
- ALK fusions represent a key oncogenic driver in a subset of lung cancers.
- Genetic epistasis plays a crucial role in the progression of ALK-driven lung cancer.
- Targeting ALK fusion partners and neoantigens offers potential alternative therapeutic avenues.
Conclusions:
- Understanding the genomic complexity of ALK rearrangements is vital for overcoming treatment resistance.
- Novel strategies targeting fusion partners and neoantigens may improve outcomes for ALK-positive lung cancer patients.
- Further research into gene-gene interactions can guide the development of next-generation therapies.
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