Diverse resistance mechanisms to the third-generation ALK inhibitor lorlatinib in ALK-rearranged lung cancer

Gonzalo Recondo, Laura Mezquita, Francesco Facchinetti, David Planchard, Anas Gazzah, Ludovic Bigot, Ahsan Z. Rizvi, Rosa L. Frias, Jean Paul Thiery, Jean Yves Scoazec, Tony Sourisseau, Karen Howarth, Olivier Deas, Dariia Samofalova, Justine Galissant, Pauline Tesson, Floriane Braye, Charles Naltet, Pernelle Lavaud, Linda MahjoubiAurelie Abou Lovergne, Gilles Vassal, Rastilav Bahleda, Antoine Hollebecque, Claudio Nicotra, Maud Ngo-Camus, Stefan Michiels, Ludovic Lacroix, Catherine Richon, Nathalie Auger, Thierry de Baere, Lambros Tselikas, Eric Solary, Eric Angevin, Alexander M. Eggermont, Fabrice Andre, Christophe Massard, Ken A. Olaussen, Jean Charles Soria, Benjamin Besse, Luc Friboulet

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

113 Citaten (Scopus)


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.

Originele taal-2Engels
Pagina's (van-tot)242-255
Aantal pagina's14
TijdschriftClinical Cancer Research
Nummer van het tijdschrift1
StatusGepubliceerd - 1 jan. 2020
Extern gepubliceerdJa


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