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Cancers 2018, 10(3), 62; https://doi.org/10.3390/cancers10030062

Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes

1
Department of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
2
Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin 10124, Italy
3
Galkem Srl, Monza 20900, Italy
4
Hematology and Clinical Research Unit, San Gerardo Hospital, Monza 20900, Italy
5
Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Received: 1 February 2018 / Revised: 25 February 2018 / Accepted: 26 February 2018 / Published: 28 February 2018
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Abstract

Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along with possible therapeutic strategies that may overcome the development of resistance. View Full-Text
Keywords: anaplastic large-cell lymphoma (ALCL); anaplastic lymphoma kinase (ALK); ALK inhibitors; non-small-cell lung cancer (NSCLC); resistance to ALK inhibitors; targeted therapies; tyrosine kinase (TK) anaplastic large-cell lymphoma (ALCL); anaplastic lymphoma kinase (ALK); ALK inhibitors; non-small-cell lung cancer (NSCLC); resistance to ALK inhibitors; targeted therapies; tyrosine kinase (TK)
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Sharma, G.G.; Mota, I.; Mologni, L.; Patrucco, E.; Gambacorti-Passerini, C.; Chiarle, R. Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes. Cancers 2018, 10, 62.

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