1
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Simple Summary

          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.

          Abstract

          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.

          Related collections

          Most cited references114

          • Record: found
          • Abstract: found
          • Article: not found

          Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial

          In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Global Cancer Incidence and Mortality Rates and Trends--An Update

            There are limited published data on recent cancer incidence and mortality trends worldwide. We used the International Agency for Research on Cancer's CANCERMondial clearinghouse to present age-standardized cancer incidence and death rates for 2003-2007. We also present trends in incidence through 2007 and mortality through 2012 for select countries from five continents. High-income countries (HIC) continue to have the highest incidence rates for all sites, as well as for lung, colorectal, breast, and prostate cancer, although some low- and middle-income countries (LMIC) now count among those with the highest rates. Mortality rates from these cancers are declining in many HICs while they are increasing in LMICs. LMICs have the highest rates of stomach, liver, esophageal, and cervical cancer. Although rates remain high in HICs, they are plateauing or decreasing for the most common cancers due to decreases in known risk factors, screening and early detection, and improved treatment (mortality only). In contrast, rates in several LMICs are increasing for these cancers due to increases in smoking, excess body weight, and physical inactivity. LMICs also have a disproportionate burden of infection-related cancers. Applied cancer control measures are needed to reduce rates in HICs and arrest the growing burden in LMICs.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              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.
                Bookmark

                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                06 November 2020
                November 2020
                : 12
                : 11
                : 3293
                Affiliations
                [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
                https://orcid.org/0000-0001-8417-9172
                https://orcid.org/0000-0003-1381-0283
                https://orcid.org/0000-0003-0093-1086
                https://orcid.org/0000-0001-5504-8237
                Article
                cancers-12-03293
                10.3390/cancers12113293
                7694780
                33172113
                44008535-d8c7-4581-8e96-f90808e2df2f
                © 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/).

                History
                : 22 September 2020
                : 05 November 2020
                Categories
                Review

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

                Comments

                Comment on this article