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 Mahjoubi; Aurelie 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

doi:10.1158/1078-0432.CCR-19-1104

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

Résultats de recherche: Contribution à un journal › Article › Revue par des pairs

124 Citations (Scopus)

Résumé

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.

langue originale	Anglais
Pages (de - à)	242-255
Nombre de pages	14
journal	Clinical Cancer Research
Volume	26
Numéro de publication	1
Les DOIs	https://doi.org/10.1158/1078-0432.CCR-19-1104
état	Publié - 1 janv. 2020

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10.1158/1078-0432.CCR-19-1104

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Recondo, G., Mezquita, L., Facchinetti, F., Planchard, D., Gazzah, A., Bigot, L., Rizvi, A. Z., Frias, R. L., Thiery, J. P., Scoazec, J. Y., Sourisseau, T., Howarth, K., Deas, O., Samofalova, D., Galissant, J., Tesson, P., Braye, F., Naltet, C., Lavaud, P., ... Friboulet, L. (2020). Diverse resistance mechanisms to the third-generation ALK inhibitor lorlatinib in ALK-rearranged lung cancer. Clinical Cancer Research, 26(1), 242-255. https://doi.org/10.1158/1078-0432.CCR-19-1104

@article{c5e10e3e8f0147708ff3064a1122a182,

title = "Diverse resistance mechanisms to the third-generation ALK inhibitor lorlatinib in ALK-rearranged lung cancer",

abstract = "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.",

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

note = "Publisher Copyright: {\textcopyright}2019 American Association for Cancer Research.",

year = "2020",

month = jan,

day = "1",

doi = "10.1158/1078-0432.CCR-19-1104",

language = "English",

volume = "26",

pages = "242--255",

journal = "Clinical Cancer Research",

issn = "1078-0432",

number = "1",

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Recondo, G, Mezquita, L, Facchinetti, F, Planchard, D, Gazzah, A, Bigot, L, Rizvi, AZ, Frias, RL, Thiery, JP, Scoazec, JY, Sourisseau, T, Howarth, K, Deas, O, Samofalova, D, Galissant, J, Tesson, P, Braye, F, Naltet, C, Lavaud, P, Mahjoubi, L, Lovergne, AA, Vassal, G, Bahleda, R, Hollebecque, A, Nicotra, C, Ngo-Camus, M, Michiels, S, Lacroix, L, Richon, C, Auger, N, de Baere, T, Tselikas, L, Solary, E, Angevin, E, Eggermont, AM, Andre, F, Massard, C, Olaussen, KA, Soria, JC, Besse, B & Friboulet, L 2020, 'Diverse resistance mechanisms to the third-generation ALK inhibitor lorlatinib in ALK-rearranged lung cancer', Clinical Cancer Research, VOL. 26, Numéro 1, p. 242-255. https://doi.org/10.1158/1078-0432.CCR-19-1104

TY - JOUR

T1 - Diverse resistance mechanisms to the third-generation ALK inhibitor lorlatinib in ALK-rearranged lung cancer

AU - Recondo, Gonzalo

AU - Mezquita, Laura

AU - Facchinetti, Francesco

AU - Planchard, David

AU - Gazzah, Anas

AU - Bigot, Ludovic

AU - Rizvi, Ahsan Z.

AU - Frias, Rosa L.

AU - Thiery, Jean Paul

AU - Scoazec, Jean Yves

AU - Sourisseau, Tony

AU - Howarth, Karen

AU - Deas, Olivier

AU - Samofalova, Dariia

AU - Galissant, Justine

AU - Tesson, Pauline

AU - Braye, Floriane

AU - Naltet, Charles

AU - Lavaud, Pernelle

AU - Mahjoubi, Linda

AU - Lovergne, Aurelie Abou

AU - Vassal, Gilles

AU - Bahleda, Rastilav

AU - Hollebecque, Antoine

AU - Nicotra, Claudio

AU - Ngo-Camus, Maud

AU - Michiels, Stefan

AU - Lacroix, Ludovic

AU - Richon, Catherine

AU - Auger, Nathalie

AU - de Baere, Thierry

AU - Tselikas, Lambros

AU - Solary, Eric

AU - Angevin, Eric

AU - Eggermont, Alexander M.

AU - Andre, Fabrice

AU - Massard, Christophe

AU - Olaussen, Ken A.

AU - Soria, Jean Charles

AU - Besse, Benjamin

AU - Friboulet, Luc

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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.

AB - 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.

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U2 - 10.1158/1078-0432.CCR-19-1104

DO - 10.1158/1078-0432.CCR-19-1104

M3 - Article

C2 - 31585938

AN - SCOPUS:85076397427

SN - 1078-0432

VL - 26

SP - 242

EP - 255

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 1

ER -