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      Focus on ROS1-Positive Non-Small Cell Lung Cancer (NSCLC): Crizotinib, Resistance Mechanisms and the Newer Generation of Targeted Therapies


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          Genetic rearrangements of the ROS1 gene account for up to 2% of NSCLC patients who sometimes develop brain metastasis, resulting in poor prognosis. This review discusses the tyrosine kinase inhibitor crizotinib plus updates and preliminary results with the newer generation of tyrosine kinase inhibitors, which have been specifically conceived to overcome crizotinib resistance, including brigatinib, cabozantinib, ceritinib, entrectinib, lorlatinib and repotrectinib. After introducing each agent’s properties, we provide suggestions on the best approaches to identify resistance mechanisms at an early stage, and we speculate on the most appropriate second-line therapies for patients who reported disease progression following crizotinib administration.


          The treatment of patients affected by non-small cell lung cancer (NSCLC) has been revolutionised by the discovery of druggable mutations. ROS1 (c-ros oncogene) is one gene with druggable mutations in NSCLC. ROS1 is currently targeted by several specific tyrosine kinase inhibitors (TKIs), but only two of these, crizotinib and entrectinib, have received Food and Drug Administration (FDA) approval. Crizotinib is a low molecular weight, orally available TKI that inhibits ROS1, MET and ALK and is considered the gold standard first-line treatment with demonstrated significant activity for lung cancers harbouring ROS1 gene rearrangements. However, crizotinib resistance often occurs, making the treatment of ROS1-positive lung cancers more challenging. A great effort has been undertaken to identify a new generation or ROS1 inhibitors. In this review, we briefly introduce the biology and role of ROS1 in lung cancer and discuss the underlying acquired mechanisms of resistance to crizotinib and the promising new agents able to overcome resistance mechanisms and offer alternative efficient therapies.

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              Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

              Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.

                Author and article information

                Cancers (Basel)
                Cancers (Basel)
                06 November 2020
                November 2020
                : 12
                : 11
                : 3293
                [1 ]Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK; bsssb@ 123456bath.ac.uk (S.B.); jbd31@ 123456bath.ac.uk (J.D.)
                [2 ]Section of Epidemiology and Population Science, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; navidsobhani19@ 123456gmail.com
                [3 ]University College London Hospitals NHS Foundation Trust, 235 Euston Rd, London NW1 2BU, UK; robert.chapman2@ 123456nhs.net
                [4 ]Department of Dermatology, University of Padova, via Vincenzo Gallucci 4, 35121 Padova, Italy; bortoletti.carlotta@ 123456gmail.com
                [5 ]Unità Operativa Anatomia Patologica, Ospedale Maggiore Carlo Alberto Pizzardi, AUSL Bologna, Largo Bartolo Nigrisoli 2, 40100 Bologna, Italy; traversini.mirko@ 123456gmail.com
                [6 ]Respiratory Medicine, Careggi University Hospital, 50139 Florence, Italy; katia3ferrari@ 123456gmail.com
                [7 ]Thoracic Surgery Unit, Careggi University Hospital, Largo Brambilla, 1, 50134 Florence, Italy; luca.voltolini@ 123456unifi.it
                [8 ]Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy; giandomenicoroviello@ 123456gmail.com
                Author notes
                [* ]Correspondence: ada43@ 123456bath.ac.uk
                Author information
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                : 22 September 2020
                : 05 November 2020

                lung cancer,solid tumours,crizotinib,toxicity,tki inhibitors,resistance mechanisms,targeted therapies,ros1,nsclc


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