Diverse Resistance Mechanisms to the Third-Generation ALK Inhibitor Lorlatinib in ALK-Rearranged Lung Cancer

Autor: Jean-Yves Scoazec, Jean-Charles Soria, Gonzalo Recondo, Aurelie Abou Lovergne, Gilles Vassal, Tony Sourisseau, Pernelle Lavaud, Justine Galissant, Nathalie Auger, Antoine Hollebecque, Laura Mezquita, Alexander M.M. Eggermont, Maud Ngo-Camus, Karen Howarth, Christophe Massard, Rastilav Bahleda, David Planchard, Rosa L. Frias, Lambros Tselikas, Anas Gazzah, Fabrice Andre, Eric Angevin, Stefan Michiels, Floriane Braye, Luc Friboulet, Ken A. Olaussen, Ahsan Z. Rizvi, Linda Mahjoubi, Ludovic Bigot, Claudio Nicotra, Francesco Facchinetti, C. Naltet, Pauline Tesson, Ludovic Lacroix, D. O. Samofalova, Benjamin Besse, Eric Solary, Catherine Richon, Thierry de Baere, Jean Paul Thiery, Olivier Deas
Rok vydání: 2019
Předmět:
0301 basic medicine
Adult
Male
Cancer Research
Epithelial-Mesenchymal Transition
Lung Neoplasms
Lactams
medicine.drug_class
Lactams
Macrocyclic
Aminopyridines
Drug resistance
Mice
SCID
Tyrosine-kinase inhibitor
Article
03 medical and health sciences
Mice
0302 clinical medicine
Mice
Inbred NOD
hemic and lymphatic diseases
Cell Line
Tumor
medicine
Anaplastic lymphoma kinase
Animals
Humans
Anaplastic Lymphoma Kinase
Epithelial–mesenchymal transition
Longitudinal Studies
Protein Kinase Inhibitors
Gene Rearrangement
Neurofibromin 2
Chemistry
Gene rearrangement
Middle Aged
Lorlatinib
Xenograft Model Antitumor Assays
3. Good health
ALK inhibitor
030104 developmental biology
Oncology
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Mutation
Cancer research
Pyrazoles
Female
Proto-oncogene tyrosine-protein kinase Src
Zdroj: Clin Cancer Res
Clinical Cancer Research
ISSN: 1557-3265
Popis: Purpose:Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor with proven efficacy in patients with ALK-rearranged lung cancer previously treated with first- and second-generation ALK inhibitors. Beside compound mutations in the ALK kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize the mechanisms of resistance to lorlatinib occurring in patients with ALK-rearranged lung cancer and design new therapeutic strategies in this setting.Experimental Design:Resistance mechanisms were investigated in 5 patients resistant to lorlatinib. Longitudinal tumor biopsies were studied using high-throughput next-generation sequencing. Patient-derived models were developed to characterize the acquired resistance mechanisms, and Ba/F3 cell mutants were generated to study the effect of novel ALK compound mutations. Drug combinatory strategies were evaluated in vitro and in vivo to overcome lorlatinib resistance.Results:Diverse biological mechanisms leading to lorlatinib resistance were identified. Epithelial–mesenchymal transition (EMT) mediated resistance in two patient-derived cell lines and was susceptible to dual SRC and ALK inhibition. We characterized three ALK kinase domain compound mutations occurring in patients, L1196M/D1203N, F1174L/G1202R, and C1156Y/G1269A, with differential susceptibility to ALK inhibition by lorlatinib. We identified a novel bypass mechanism of resistance caused by NF2 loss-of-function mutations, conferring sensitivity to treatment with mTOR inhibitors.Conclusions:This study shows that mechanisms of resistance to lorlatinib are diverse and complex, requiring new therapeutic strategies to tailor treatment upon disease progression.
Databáze: OpenAIRE
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