PMID- 30290287
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 1936-5233 (Print)
IS  - 1936-5233 (Electronic)
IS  - 1936-5233 (Linking)
VI  - 12
IP  - 1
DP  - 2019 Jan
TI  - MYC Amplification as a Potential Mechanism of Primary Resistance to Crizotinib in 
      ALK-Rearranged Non-Small Cell Lung Cancer: A Brief Report.
PG  - 116-121
LID - S1936-5233(18)30384-X [pii]
LID - 10.1016/j.tranon.2018.09.013 [doi]
AB  - INTRODUCTION: Translocations of the anaplastic lymphoma kinase (ALK) can be 
      effectively targeted in advanced non-small cell lung cancer by ALK-TKI inhibitors 
      including Crizotinib. However, the development of acquired resistance often 
      limits the duration of these therapies. While several mechanisms of secondary 
      resistance have been already identified, little is known about molecular 
      determinants of primary resistance. In our brief report we investigated the tumor 
      molecular profile of a patient who failed to respond to Crizotinib. METHODS: 
      Fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) 
      were run on tumor specimen as well as search and characterization of circulating 
      tumor cells (CTCs) in the blood. Confirmation of clinical findings was achieved 
      using a translational cell-line in vitro model. RESULTS: We identified the 
      amplification of MYC as a potential new mechanism of primary resistance to ALK 
      inhibition. Human EML4-ALK rearranged cells infected with a lentiviral vector 
      carrying full-length human MYC cDNA were treated in vitro with crizotinib and 
      alectinib. Overexpression of MYC overexpression was associated with a reduced 
      sensitivity to both ALK-inhibitors. MYC-overexpressing clones displayed also 
      increased levels of both cyclin D and E and their growth was reduced by using 
      Cdk4/6 inhibitors such as Palbociclib. CONCLUSIONS: We postulate that the MYC 
      gene may be implicated in the mechanism of primary resistance to ALK inhibitors. 
      We also suggest potential MYC-directed inhibition strategies to overcome primary 
      resistance in advanced ALK-rearranged NSCLC.
CI  - Copyright (c) 2018 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Rihawi, Karim
AU  - Rihawi K
AD  - Department of Experimental, Diagnostic and Specialty Medicine DIMES - University 
      of Bologna, Via Massarenti 9, 40138, Bologna, Italy; Medical Oncology, 
      S.Orsola-Malpighi University Hospital and Alma Mater University of Bologna, Via 
      Massarenti 9, 40138, Bologna, Italy.
FAU - Alfieri, Roberta
AU  - Alfieri R
AD  - Experimental Oncology Laboratory, Department of Medicine and Surgery, University 
      of Parma, Via Gramsci, 14, 43126, Italy.
FAU - Fiorentino, Michelangelo
AU  - Fiorentino M
AD  - Department of Experimental, Diagnostic and Specialty Medicine DIMES - University 
      of Bologna, Via Massarenti 9, 40138, Bologna, Italy; Molecular Pathology, 
      S.Orsola-Malpighi University Hospital and Alma Mater University of Bologna, Via 
      Massarenti 9, 40138, Bologna, Italy. Electronic address: 
      michelangelo.fiorentino@unibo.it.
FAU - Fontana, Francesca
AU  - Fontana F
AD  - Menarini Silicon Biosystems SpA, Via Giuseppe di Vittorio 21, 40013, Castel 
      Maggiore, Italy.
FAU - Capizzi, Elisa
AU  - Capizzi E
AD  - Department of Experimental, Diagnostic and Specialty Medicine DIMES - University 
      of Bologna, Via Massarenti 9, 40138, Bologna, Italy; Molecular Pathology, 
      S.Orsola-Malpighi University Hospital and Alma Mater University of Bologna, Via 
      Massarenti 9, 40138, Bologna, Italy.
FAU - Cavazzoni, Andrea
AU  - Cavazzoni A
AD  - Experimental Oncology Laboratory, Department of Medicine and Surgery, University 
      of Parma, Via Gramsci, 14, 43126, Italy.
FAU - Terracciano, Mario
AU  - Terracciano M
AD  - Menarini Silicon Biosystems SpA, Via Giuseppe di Vittorio 21, 40013, Castel 
      Maggiore, Italy.
FAU - La Monica, Silvia
AU  - La Monica S
AD  - Experimental Oncology Laboratory, Department of Medicine and Surgery, University 
      of Parma, Via Gramsci, 14, 43126, Italy.
FAU - Ferrarini, Alberto
AU  - Ferrarini A
AD  - Menarini Silicon Biosystems SpA, Via Giuseppe di Vittorio 21, 40013, Castel 
      Maggiore, Italy.
FAU - Buson, Genny
AU  - Buson G
AD  - Menarini Silicon Biosystems SpA, Via Giuseppe di Vittorio 21, 40013, Castel 
      Maggiore, Italy.
FAU - Petronini, Pier Giorgio
AU  - Petronini PG
AD  - Experimental Oncology Laboratory, Department of Medicine and Surgery, University 
      of Parma, Via Gramsci, 14, 43126, Italy.
FAU - Ardizzoni, Andrea
AU  - Ardizzoni A
AD  - Department of Experimental, Diagnostic and Specialty Medicine DIMES - University 
      of Bologna, Via Massarenti 9, 40138, Bologna, Italy; Medical Oncology, 
      S.Orsola-Malpighi University Hospital and Alma Mater University of Bologna, Via 
      Massarenti 9, 40138, Bologna, Italy.
LA  - eng
PT  - Journal Article
DEP - 20181002
PL  - United States
TA  - Transl Oncol
JT  - Translational oncology
JID - 101472619
PMC - PMC6171095
EDAT- 2018/10/06 06:00
MHDA- 2018/10/06 06:01
PMCR- 2018/10/02
CRDT- 2018/10/06 06:00
PHST- 2018/08/18 00:00 [received]
PHST- 2018/09/24 00:00 [revised]
PHST- 2018/09/24 00:00 [accepted]
PHST- 2018/10/06 06:00 [pubmed]
PHST- 2018/10/06 06:01 [medline]
PHST- 2018/10/06 06:00 [entrez]
PHST- 2018/10/02 00:00 [pmc-release]
AID - S1936-5233(18)30384-X [pii]
AID - 10.1016/j.tranon.2018.09.013 [doi]
PST - ppublish
SO  - Transl Oncol. 2019 Jan;12(1):116-121. doi: 10.1016/j.tranon.2018.09.013. Epub 
      2018 Oct 2.