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Lorlatinib Treatment Elicits Multiple On- and Off-Target Mechanisms of Resistance in ALK-Driven Cancer Sara Redaelli1, Monica Ceccon1, Marina Zappa1, Geeta G

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Lorlatinib Treatment Elicits Multiple On- and Off-Target Mechanisms of Resistance in ALK-Driven Cancer Sara Redaelli1, Monica Ceccon1, Marina Zappa1, Geeta G Published OnlineFirst October 15, 2018; DOI: 10.1158/0008-5472.CAN-18-1867 Cancer Translational Science Research Lorlatinib Treatment Elicits Multiple On- and Off-Target Mechanisms of Resistance in ALK-Driven Cancer Sara Redaelli1, Monica Ceccon1, Marina Zappa1, Geeta G. Sharma1,2, Cristina Mastini1, Mario Mauri1, Marion Nigoghossian1,3, Luca Massimino1, Nicoletta Cordani1,4, Francesca Farina4, Rocco Piazza1,4, Carlo Gambacorti-Passerini1,2,4, and Luca Mologni1,2 Abstract Targeted therapy changed the standard of care in Functional validation by small-molecule inhibitors con- ALK-dependent tumors. However, resistance remains a major firmed the involvement of these pathways in resistance to challenge. Lorlatinib is a third-generation ALK inhibitor that lorlatinib. NSCLC cells exposed in vitro to lorlatinib inhibits most ALK mutants resistant to current ALK inhibitors. acquired hyperactivation of EGFR, which was blocked by In this study, we utilize lorlatinib-resistant anaplastic large cell erlotinibtorestoresensitivity to lorlatinib. In neuroblasto- lymphoma (ALCL), non–small cell lung cancer (NSCLC), and ma, whole-exome sequencing and proteomic profiling of neuroblastoma cell lines in vitro and in vivo to investigate the lorlatinib-resistant cells revealed a truncating NF1 mutation acquisition of resistance and its underlying mechanisms. ALCL and hyperactivation of EGFR and ErbB4. These data provide cells acquired compound ALK mutations G1202R/G1269A an extensive characterization of resistance mechanisms that and C1156F/L1198F in vitro at high drug concentrations. ALCL may arise in different ALK-positive cancers following lorla- xenografts selected in vivo showed recurrent N1178H tinib treatment. (5/10 mice) and G1269A (4/10 mice) mutations. Interesting- ly, intracellular localization of NPM/ALKN1178H skewed Significance: High-throughput genomic, transcriptomic, toward the cytoplasm in human cells, possibly mimicking and proteomic profiling reveals various mechanisms by which overexpression. RNA sequencing of resistant cells showed multiple tumor types acquire resistance to the third-generation significant alteration of PI3K/AKT and RAS/MAPK pathways. ALK inhibitor lorlatinib. Cancer Res; 78(24); 6866–80. Ó2018 AACR. Introduction Several novel compounds were developed, by improving potency, selectivity, and brain penetration. Among these, lorlatinib Activation of the anaplastic lymphoma kinase (ALK) is (PF-06463922, a third-generation ALKi) showed activity against involved in the pathogenesis of different cancers, including ana- most drug-resistant mutants, including the highly refractory plastic large cell lymphoma (ALCL), non–small cell lung cancer G1202R mutant (8–11). Indeed, ceritinib-resistant patient- (NSCLC) and neuroblastoma (1). ALK inhibitors (ALKi) were derived cells carrying EML4/ALK mutations were shown to be developed for specific treatment of ALK-positive patients (1, 2). sensitive to lorlatinib, while cells without ALK mutations were Crizotinib demonstrated superior activity compared with chemo- resistant (12), suggesting that resistance to this drug might arise therapy in NSCLC and showed exceptional response rates in from ALK-independent processes bypassing ALK dependency, as refractory ALCL and inflammatory myofibroblastic tumor (IMT) observed in a fraction of patients with NSCLC treated with other patients (3–5). Unfortunately, the selection of drug-resistant ALKi (6, 7, 13, 14). In such cases, drug combinations could clones has limited the long-term efficacy of crizotinib, especially provide effective therapeutic options (15, 16). On the other hand, in NSCLC (1, 6, 7). The knowledge of resistance mechanisms compound mutations may also represent a big challenge, still guided the quest for new drugs to overcome crizotinib failure. poorly characterized. Indeed, a C1156Y/L1198F mutation was found in a patient relapsed on lorlatinib (17). Therefore, under- 1 standing the mechanisms leading to tumor escape is a key to the School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy. development of better therapeutic choices. 2European Research Initiative for ALK-Related Malignancies (ERIA), Cambridge, United Kingdom. 3University Claude Bernard Lyon 1, Villeurbanne, France. In this work, we investigated the spectrum of possible resistance 4Hematology and Clinical Research Unit, San Gerardo Hospital, Monza, Italy. mechanisms arising during lorlatinib treatment in ALK-dependent tumors. To this end, we kept ALCL, NSCLC, and neuroblastoma Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). cells under selective pressure until drug-resistant clones evolved, in vitro and in vivo, from the original cell population. S. Redaelli and M. Ceccon contributed equally to this article. Corresponding Author: Luca Mologni, School of Medicine and Surgery, Univer- sity of Milano-Bicocca, via Cadore 48, Monza 20900, Italy. Phone: 3902-6448- Materials and Methods 8148; Fax: 3902-6448-8363; E-mail: [email protected] Chemicals and cell lines doi: 10.1158/0008-5472.CAN-18-1867 Lorlatinib and crizotinib were provided by Pfizer. Ceritinib, Ó2018 American Association for Cancer Research. erlotinib, afatinib, alectinib, and trametinib were purchased from 6866 Cancer Res; 78(24) December 15, 2018 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst October 15, 2018; DOI: 10.1158/0008-5472.CAN-18-1867 Resistance to Lorlatinib in ALK-Dependent Cancer Selleck Chemicals. Karpas-299, SUP-M2, and HEK-293T cells Brilliant-III Ultra-Fast SYBR Green QPCR Master Mix (Agilent). were purchased from DSMZ, where they were routinely verified Primers are reported in Supplementary Table S1. TaqMan qPCR using genotypic and phenotypic testing to confirm their identity. for EGFR (Hs01076090_m1), ERBB4 (Hs00955522_m1), and H3122 and H2228 cell lines were provided by Dr. Claudia Voena ABCG2 (Hs01053790_m1) was performed using Brilliant-II (University of Turin, Turin, Italy). CLB-GA cells were provided by QPCR Master Mix (Agilent) and probe mixes from Thermo Fisher Dr. Valerie Combaret (Leon Berard Cancer Centre, Lyon, France). Scientific. The beta-glucuronidase (GUS) gene was used as a Mycoplasma testing is routinely conducted on all cell lines in the reference (probe 50-CCAGCACTCTCGTCGGTGACTGTTCA-30). laboratory. For mutation analysis, ALK kinase domain was amplified by High Fidelity Taq Polymerase (Roche) using primers shown in Sup- Antibodies plementary Table S1. Purified PCR products were sent for Sanger The following antibodies were purchased from Cell Signaling sequencing to GATC Biotech or cloned by TOPO TA Cloning Kit Technology: ALK (31F12), EGFR, S6 ribosomal protein (RPS6), (Invitrogen) and sequenced. Compound mutations were always p44/42 MAPK (Erk1/2), STAT3, HER4/ErbB4 (111B2), AKT, confirmed by clonal Sanger sequencing. For ultra-deep sequenc- phospho-ALK (Tyr1604), phospho-ALK (Tyr1278), phospho- ing, NPM-ALK kinase domain was amplified from parental and EGFR (Tyr1068), phospho-RPS6 (Ser240/244), phospho-STAT3 resistant cells using High Fidelity Taq Polymerase (Roche) and (Tyr705), phospho-p44/42 MAPK (Erk1/2; Thr202/Tyr204), NPM-ALK KD primers (Supplementary Table S1). Amplicons phospho-HER4/ErbB4 (Tyr1284; 21A9), phospho-AKT (Ser473), were purified from agarose gel and sent to GalSeq for sequencing phospho-AKT (Thr308; D25E6). Anti-phosphotyrosine (PY20) at 10,000Â mean coverage. Fastq files were aligned onto the and anti-actin antibodies were purchased from Sigma-Aldrich, reference ALK transcript. Integrative Genomics Viewer (IGV; and anti-tubulin was from Abcam. All antibodies were used at Broad Institute, Cambridge, MA) was used to visualize the data 1:1,000 dilution, except anti-actin (1:2,000). and annotate variants. Resistant cell–specific mutations were identified by filtering against parental cells' data. Whole-exome In vitro selection of lorlatinib-resistant cells sequencing (WES) and RNA-sequencing were performed as Lorlatinib-resistant cell lines were established in vitro by expos- described previously (19). Briefly, genomic DNA was extracted ing cells to gradually increasing drug concentrations, as described from control and resistant cells using PureLink Genomic DNA previously (18). To monitor cell culture growth, ALCL cell num- Mini Kit (Invitrogen) and sent to GalSeq srl for sequencing at ber and viability were tracked by Trypan Blue count every other mean coverage 80Â. Fastq files were aligned on reference human day, while confluency was estimated under the microscope for genome (hg38) and analyzed by CEQer2, an evolution of CEQer adherent cells. Every time the cells resumed proliferation rates (20). Variants were called if present in >25% of resistant cells reads comparable with parental cells, drug concentration was increased. and <5% of control reads. Synonymous and noncoding substitu- tions were discarded. Variants with <20Â coverage in either In vivo studies control or case samples were filtered out. For RNA-sequencing, For selection of resistant tumors in vivo, 6-week-old female scid total RNA was extracted from three independent vehicle-treated mice (C.B.17/IcrHanHsd-Prkdc) were purchased from Envigo Lab- control K299 xenografts, and three lorlatinib-resistant tumors oratories (San Pietro al Natisone, Udine, Italy) and kept under (AS4, BS1, and BD1) using TRIzol reagent, following the standard conditions following the guidelines of the University of standard protocol. Samples
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