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Review
. 2022 Sep 29;14(19):4765.
doi: 10.3390/cancers14194765.

The Landscape of ALK-Rearranged Non-Small Cell Lung Cancer: A Comprehensive Review of Clinicopathologic, Genomic Characteristics, and Therapeutic Perspectives

Valeria Cognigni  1 , Federica Pecci  1 , Alessio Lupi  1 , Giada Pinterpe  1 , Chiara De Filippis  1 , Cristiano Felicetti  1 , Luca Cantini  1 , Rossana Berardi  1
Affiliations
Review

The Landscape of ALK-Rearranged Non-Small Cell Lung Cancer: A Comprehensive Review of Clinicopathologic, Genomic Characteristics, and Therapeutic Perspectives

Valeria Cognigni et al. Cancers (Basel). .

Abstract

During the last decade, the identification of oncogenic driver mutations and the introduction of tyrosine kinase inhibitors (TKIs) in daily clinical practice have substantially revamped the therapeutic approach of oncogene-addicted, non-small cell lung cancer (NSCLC). Rearrangements in the anaplastic lymphoma kinase (ALK) gene are detected in around 3-5% of all NSCLC patients. Following the promising results of Crizotinib, a first-generation ALK inhibitor (ALK-i), other second-generation and more recently third-generation TKIs have been developed and are currently a landmark in NSCLC treatment, leading to a significant improvement in patients prognosis. As clinical trials have already demonstrated high efficacy of each ALK-i, both in terms of systemic and intracranial disease control, comparative studies between second and third generation ALK-i are still lacking, and primary or secondary ALK-i resistance inevitably limit their efficacy. Resistance to ALK-i can be due to ALK-dependent or ALK-independent mechanisms, including the activation of bypass signaling pathways and histological transformation: these findings may play an important role in the future to select patients' subsequent therapy. This review aims to provide an overview of underlying molecular alterations of ALK-i resistance and point out promising role of liquid biopsy in predicting tumor response and monitoring resistance mutations. The purpose of this review is also to summarize current approval for ALK-rearranged NSCLC patients, to help clinicians in making decisions on therapeutic sequence, and to deepen the role of clinicopathological and genomic characteristics influencing patients' prognosis during treatment with ALK-i.

Keywords: ALK inhibitors; anaplastic lymphoma kinase (ALK); liquid biopsy; non-small cell lung cancer (NSCLC); resistance mechanism.

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Conflict of interest statement

Rossana Berardi is a consultant/advisory board member for AstraZeneca, Boehringer Ingelheim, Novartis, MSD, Otsuka, Eli-Lilly, Roche. All other authors declare that there is no conflict of interest.

Figures

Figure 1
Figure 1
The EML4-ALK gene fusions: three major EML4-ALK variants are represented here, showing where the ALK kinase domain is inserted into the EML4 protein. Breakpoints in EML4 and ALK that generate different variants are marked with black arrows. Abbreviations: ALK, anaplastic lymphoma kinase; EMAP, echinoderm microtubule-associated protein; EML4, echinoderm microtubule-associated protein like 4; GR, glycine-rich region; LDLa, low-density lipoprotein alpha domain; MAM, meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu; TD, trimerisation domain; WD, tryptophan-aspartic acid region; TM, trans-membrane region.
Figure 2
Figure 2
Approval timeline of currently available ALK inhibitors.
Figure 3
Figure 3
Mechanisms of resistance to ALK- inhibitors, including on-target and off-target molecular mechanisms. Abbreviations: ALK-i, ALK inhibitors; EMT, epithelial-to-mesenchymal transition; SCLC, small-cell lung cancer; SCC, squamous cell carcinoma.
See this image and copyright information in PMC

References

    1. Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer J. Clin. 2021;71:209–249. doi: 10.3322/caac.21660. - DOI - PubMed
    1. McKeage M.J., Tin Tin S., Khwaounjoo P., Sheath K., Dixon-McIver A., Ng D., Sullivan R., Cameron L., Shepherd P., Laking G.R., et al. Screening for Anaplastic Lymphoma Kinase (ALK) Gene Rearrangements in Non-Small-Cell Lung Cancer in New Zealand. Intern. Med. J. 2020;50:716–725. doi: 10.1111/imj.14435. - DOI - PubMed
    1. Allen T.C., Xiao Y., Yang B., Croix D., Abraham A., Redpath S., Engstrom-Melynk J., Shah R., Madala J., Bernicker E.H. Anaplastic Lymphoma Kinase Rearrangement Prevalence in Patients with Advanced Non-Small Cell Lung Cancer in the United States: Retrospective Real World Data. Oncotarget. 2021;12:2308. doi: 10.18632/oncotarget.28114. - DOI - PMC - PubMed
    1. Rangachari D., Yamaguchi N., VanderLaan P.A., Folch E., Mahadevan A., Floyd S.R., Uhlmann E.J., Wong E.T., Dahlberg S.E., Huberman M.S., et al. Brain Metastases in Patients with EGFR-Mutated or ALK-Rearranged Non-Small-Cell Lung Cancers. Lung Cancer. 2015;88:108–111. doi: 10.1016/j.lungcan.2015.01.020. - DOI - PMC - PubMed
    1. Griesinger F., Roeper J., Pöttgen C., Willborn K.C., Eberhardt W.E.E. Brain Metastases in ALK-Positive NSCLC—Time to Adjust Current Treatment Algorithms. Oncotarget. 2018;9:35181. doi: 10.18632/oncotarget.26073. - DOI - PMC - PubMed