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Cancers 2017, 9(12), 164; doi:10.3390/cancers9120164

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

1
Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115, USA
2
Department of Medicine, University of California, San Francisco, CA 94115, USA
*
Author to whom correspondence should be addressed.
Received: 2 October 2017 / Revised: 14 November 2017 / Accepted: 28 November 2017 / Published: 30 November 2017
(This article belongs to the Special Issue Targeting ALK in Cancer)
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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. View Full-Text
Keywords: anaplastic lymphoma kinase; ALK; dimerization inhibition; neoantigens; CAR-T; immunotherapy anaplastic lymphoma kinase; ALK; dimerization inhibition; neoantigens; CAR-T; immunotherapy
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Wu, W.; Haderk, F.; Bivona, T.G. Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung Cancer. Cancers 2017, 9, 164.

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