Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung Cancer

Anaplastic lymphoma kinase ( ) 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...

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Bibliographic Details
Published in:Cancers 2017-11, Vol.9 (12), p.164
Main Authors: Wu, Wei, Haderk, Franziska, Bivona, Trever G
Format: Article
Language:English
Subjects:
Drug resistance
Epistasis
Kinases
Lung cancer
Lymphoma
Mutation
Neoantigens
Oncoproteins
Protein-tyrosine kinase
Proteins
Review
Tumorigenesis
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Summary:Anaplastic lymphoma kinase ( ) 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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers9120164