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.

MYC Amplification as a Potential Mechanism of Primary Resistance to Crizotinib in ALK-Rearranged Non-Small Cell Lung Cancer: A Brief Report / Rihawi, Karim; Alfieri, Roberta; Fiorentino, Michelangelo; Fontana, Francesca; Capizzi, Elisa; Cavazzoni, Andrea; Terracciano, Mario; La Monica, Silvia; Ferrarini, Alberto; Buson, Genny; Petronini, Pier Giorgio; Ardizzoni, Andrea. - In: TRANSLATIONAL ONCOLOGY. - ISSN 1936-5233. - STAMPA. - 12:1(2019), pp. 116-121. [10.1016/j.tranon.2018.09.013]

MYC Amplification as a Potential Mechanism of Primary Resistance to Crizotinib in ALK-Rearranged Non-Small Cell Lung Cancer: A Brief Report

Rihawi, Karim;Fiorentino, Michelangelo;Capizzi, Elisa;Ardizzoni, Andrea
2019

Abstract

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.
2019
MYC Amplification as a Potential Mechanism of Primary Resistance to Crizotinib in ALK-Rearranged Non-Small Cell Lung Cancer: A Brief Report / Rihawi, Karim; Alfieri, Roberta; Fiorentino, Michelangelo; Fontana, Francesca; Capizzi, Elisa; Cavazzoni, Andrea; Terracciano, Mario; La Monica, Silvia; Ferrarini, Alberto; Buson, Genny; Petronini, Pier Giorgio; Ardizzoni, Andrea. - In: TRANSLATIONAL ONCOLOGY. - ISSN 1936-5233. - STAMPA. - 12:1(2019), pp. 116-121. [10.1016/j.tranon.2018.09.013]
Rihawi, Karim; Alfieri, Roberta; Fiorentino, Michelangelo; Fontana, Francesca; Capizzi, Elisa; Cavazzoni, Andrea; Terracciano, Mario; La Monica, Silvia; Ferrarini, Alberto; Buson, Genny; Petronini, Pier Giorgio; Ardizzoni, Andrea
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/655635
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