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

被引：128

作者：

Recondo, Gonzalo ^{[1
,2
]}

Mezquita, Laura ^{[3
]}

Facchinetti, Francesco ^{[1
,2
]}

Planchard, David ^{[3
]}

Gazzah, Anas ^{[4
]}

Bigot, Ludovic ^{[1
,2
]}

Rizvi, Ahsan Z. ^{[1
,2
]}

Frias, Rosa L. ^{[1
,2
]}

Thiery, Jean Paul ^{[5
,6
,7
,8
,9
]}

Scoazec, Jean-Yves ^{[2
,10
,11
,12
]}

Sourisseau, Tony ^{[1
,2
]}

Howarth, Karen ^{[13
]}

Deas, Olivier ^{[14
]}

Samofalova, Dariia ^{[15
,16
]}

Galissant, Justine ^{[1
,2
]}

Tesson, Pauline ^{[1
,2
]}

Braye, Floriane ^{[1
,2
]}

Naltet, Charles ^{[3
]}

Lavaud, Pernelle ^{[3
]}

Mahjoubi, Linda ^{[4
]}

Abou Lovergne, Aurelie ^{[2
,17
]}

Vassal, Gilles ^{[17
]}

Bahleda, Rastilav ^{[4
]}

Hollebecque, Antoine ^{[4
]}

Nicotra, Claudio ^{[4
]}

Ngo-Camus, Maud ^{[4
]}

Michiels, Stefan ^{[18
]}

Lacroix, Ludovic ^{[1
,2
,10
,11
,12
]}

Richon, Catherine ^{[10
,11
]}

Auger, Nathalie ^{[12
]}

De Baere, Thierry ^{[19
]}

Tselikas, Lambros ^{[19
]}

Solary, Eric ^{[20
]}

Angevin, Eric ^{[4
]}

Eggermont, Alexander M. ^{[3
]}

Andre, Fabrice ^{[1
,2
,3
]}

Massard, Christophe ^{[1
,2
,4
]}

Olaussen, Ken A. ^{[1
,2
]}

Soria, Jean-Charles ^{[1
,2
,4
]}

Besse, Benjamin ^{[1
,2
,3
]}

Friboulet, Luc ^{[1
,2
]}

机构：

[1] Gustave Roussy Canc Campus, INSERM, U981, Villejuif, France

[2] Univ Paris Saclay, Paris, France

[3] Gustave Roussy Canc Campus, Dept Med Oncol, Villejuif, France

[4] Gustave Roussy Canc Campus, Drug Dev Dept DITEP, Villejuif, France

[5] Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore, Singapore

[6] Chinese Acad Sci, Inst Biomed & Hlth, Beijing, Peoples R China

[7] Univ Bergen, Fac Med & Dent, Dept Clin Med, CCBIO, Bergen, Norway

[8] Univ Hong Kong, Li Ka Shing Fac Med, Dept Clin Oncol, Hong Kong, Peoples R China

[9] Univ Paris Denis Diderot, CNRS, UMR Matter & Complex Syst 7057, Paris, France

[10] Gustave Roussy Canc Campus, Expt & Translat Pathol Platform PETRA, Genom Platform Mol Biopathol Unit BMO, Villejuif, France

[11] Gustave Roussy Canc Campus, CNRS, AMMICA, INSERM,US23,UMS3655,Biol Resource Ctr, Villejuif, France

[12] Gustave Roussy Canc Campus, Dept Med Biol & Pathol, Villejuif, France

[13] Inivata, Granta Pk, England

[14] XenTech, Evry, France

[15] Life Chem Inc, Niagara On The Lake, ON, Canada

[16] NAS Ukraine, Inst Food Biotechnol & Genom, Kiev, Ukraine

[17] Gustave Roussy Canc Campus, Dept Clin Res, Villejuif, France

[18] Gustave Roussy Canc Campus, Dept Biostat & Epidemiol, Villejuif, France

[19] Gustave Roussy Canc Campus, Dept Intervent Radiol, Villejuif, France

[20] Gustave Roussy Canc Campus, Dept Hematol, Villejuif, France

来源：

CLINICAL CANCER RESEARCH | 2020年 / 26卷 / 01期

基金：

欧洲研究理事会;

关键词：

TO-MESENCHYMAL TRANSITION; CRIZOTINIB RESISTANCE; GENOMICS; KINASE; CELLS; SRC;

D O I：

10.1158/1078-0432.CCR-19-1104

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：242 / 255

页数：14

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