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Resistance Mechanisms to Targeted Therapies in ROS1+ and ALK+ Non−Small Cell Lung Cancer

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Resistance Mechanisms to Targeted Therapies in ROS1+ and ALK+ Non−Small Cell Lung Cancer Published OnlineFirst April 10, 2018; DOI: 10.1158/1078-0432.CCR-17-2452 Cancer Therapy: Clinical Clinical Cancer Research Resistance Mechanisms to Targeted Therapies in ROS1þ and ALKþ Non–small Cell Lung Cancer Caroline E. McCoach1, Anh T. Le2, Katherine Gowan3, Kenneth Jones3, Laura Schubert2, Andrea Doak2, Adriana Estrada-Bernal2, Kurtis D. Davies4, Daniel T. Merrick4, Paul A. BunnJr2, W. Tom Purcell2, Rafal Dziadziuszko5, Marileila Varella-Garcia2, Dara L. Aisner4, D. Ross Camidge2, and Robert C. Doebele2 Abstract Purpose: Despite initial benefit from tyrosine kinase inhibitors and b-catenin mutations and HER2-mediated bypass signaling as þ (TKIs), patients with advanced non–smallcelllungcancer(NSCLC) non-ROS1–dominant resistance mechanisms. In the ALK þ þ harboring ALK (ALK )andROS1 (ROS1 ) gene fusions ultimately cohort, we identified a novel NRG1 gene fusion, a RET fusion, progress. Here, we report on the potential resistance mechanisms 2 EGFR, and 3 KRAS mutations, as well as mutations in IDH1, þ þ in a series of patients with ALK and ROS1 NSCLC progressing RIT1, NOTCH, and NF1. In addition, we identified CNV in on different types and/or lines of ROS1/ALK–targeted therapy. multiple proto-oncogenes genes including PDGFRA, KIT, KDR, Experimental Design: We used a combination of next-gener- GNAS, K/HRAS, RET, NTRK1, MAP2K1, and others. ation sequencing (NGS), multiplex mutation assay, direct DNA Conclusions: We identified a putative TKI resistance mech- þ sequencing, RT-PCR, and FISH to identify fusion variants/partners anism in six of 12 (50%) ROS1 patients and 37 of 43 (86%) þ and copy-number gain (CNG), kinase domain mutations (KDM), ALK patients. Our data suggest that a focus on KDMs will and copy-number variations (CNVs) in other cancer-related miss most resistance mechanisms; broader gene testing strat- þ þ genes. We performed testing on 12 ROS1 and 43 ALK patients. egies and functional validation is warranted to devise new þ þ Results: One of 12 ROS1 (8%) and 15 of 43 (35%) ALK therapeutic strategies for drug resistance. Clin Cancer Res; 1–14. þ patients harbored KDM. In the ROS1 cohort, we identified KIT Ó2018 AACR. Introduction Treatment of patients with NSCLC whose tumors harbor ROS1 and ALK fusions using cognate tyrosine kinase inhibitors Large-scale chromosomal alterations involving c-ros onco- (TKI) has allowed for dramatic improvements in response rates, gene 1 (ROS1) or the anaplastic lymphoma kinase (ALK) progression-free survival, and overall survival compared with exhibit oncogenic activity in non–smallcelllungcancer chemotherapy (12–16). Crizotinib, the first FDA-approved TKI (NSCLC; refs. 1–3). ROS1 and ALK gene fusions result in the þ þ for ALK and the only FDA-approved TKI for ROS1 patients, expression of chimeric proteins that constitutively activate þ demonstrated a PFS of 9.7 months in ALK patients and 19.2 downstream proliferation and survival pathways (2, 4, 5). þ months in ROS1 patients, both studies enrolled patients with Thesefusionscanbedetectedbymultiplemethodsincluding and without prior lines of therapy (3, 16). Ceritinib, alectinib, FISH, RT-PCR with direct sequencing, next-generation sequenc- þ and brigatinib have also been approved for ALK patients ing (NGS), and IHC (6–11). who have progressed on crizotinib and these drugs demon- strated response rates in the second-line setting of 56%, 50%, þ and 54%, respectively (17–19). In ROS1 patients who pro- gressed on crizotinib, there are no FDA-approved TKIs; how- 1Division of Medical Oncology, UCSF Helen Diller Comprehensive Cancer Center, San Francisco, California. 2Division of Medical Oncology, Department of Med- ever, multiple drugs including ceritinib, brigatinib, lorlatinib, icine, University of Colorado School of Medicine, Aurora, Colorado. 3Department and cabozantinib are being evaluated as post-crizotinib options þ of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplant, (20–23). For ALK patients, there are also multiple new ALK- University of Colorado, Aurora, Colorado. 4Department of Pathology, University targeted TKIs that are currently being investigated, including 5 of Colorado School of Medicine, Aurora, Colorado. Department of Oncology lorlatinib and ensartinib (24–28). and Radiotherapy, Medical University of Gdansk, Gdansk, Poland. Our group and others have previously reported on the þ Note: Supplementary data for this article are available at Clinical Cancer mechanisms of crizotinib resistance in ALK patients, which Research Online (http://clincancerres.aacrjournals.org/). include somatic mutations in the kinase domain (KDM), Corresponding Author: Caroline E. McCoach, Division of Medical Oncology, gene copy-number gains (CNGs), and alternate oncogenic UCSF Helen Diller Comprehensive Cancer Center, 1600 Divisadero St, MS 1770, mutations (29, 30). In addition, series describing the resis- San Francisco, CA 94143. Phone: 650-207-9216; Fax: 415-353-7984; E-mail: tance mechanisms to next-generation ALK TKIs have been þ [email protected] recently published; however, many ALK tumors did not doi: 10.1158/1078-0432.CCR-17-2452 have an identifiable mechanism of resistance (30–34). Cur- Ó2018 American Association for Cancer Research. rently, little is known about resistance mechanisms in patients www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on October 3, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst April 10, 2018; DOI: 10.1158/1078-0432.CCR-17-2452 McCoach et al. Hyper Prep Kit (Kapa Biosystems). The average read depth for Translational Relevance each region was 2,233 independent reads. þ þ Patients with ROS1 and ALK non–small cell lung cancer ROS1 exons 36–42 and ALK exons 21–25 were sequenced to treated with oncogene-targeted therapy will inevitably develop detect kinase domain mutations and average read depth for each drug resistance and disease progression. Two general biolog- exon is shown in Supplementary Table S2. Coverage for ALK ical mechanisms of resistance are described: alterations that intron 19, the most common breakpoint region, is also shown restore signaling through the original oncogene driver in the in Supplementary Table S2. presence of the drug or alterations that switch dependence to other signaling pathways. Currently, little is known about Bioinformatics analysis ROS1 resistance and the spectrum of ALK resistance mechan- A bioinformatics pipeline was utilized in which sequence isms may be changing with the introduction of new inhibitors. reads were analyzed using the Genomic Short Read Nucleotide As specific resistance mechanisms could influence subsequent Alignment Program (GSNAP) and the "Clipping REveals drug treatment choices and future drug combination strate- STructure" (CREST) algorithm to identify structural rearran- gies, data on the type and frequency of different resistance gements (35, 36). We calculated copy-number variation þ þ mechanisms for ROS1 and ALK cancers are likely to become (CNV) for each gene locus by first calculating the number of increasingly important. Our data suggest comprehensive unique reads for each gene in each tumor sample and taking methods, beyond the identification of kinase domain muta- the average of all 48 genes in that sample. The number of tions, are needed to identify the full spectrum of drug resis- unique reads for each gene locus was then normalized to this þ þ tance in ROS1 and ALK cancer. 48-gene average to account for differences in depth of cover- age between each sample. Non-ALK and -ROS1 cohort sam- ples were utilized in this analysis to improve the reliability of the median unique reads at each locus. A value that was þ greater than 2.5 SDs from the median unique read count at with ROS1 NSCLC after treatment with crizotinib and/or each locus was chosen as the cutoff for a significant increase. other ROS1 TKIs. Here, we report on the potential resist- þ þ Gitools version 2.3.1 (available at www.gitools.org) was used ance mechanisms of cohorts of ROS1 and ALK NSCLC to generate heatmaps. patients treated across multiple lines of therapy and with different TKIs. Direct sequencing, SNaPshot, and anchored-multiplexed PCR Materials and Methods As described previously, genomic DNA was isolated from Patient population manually microdissected FFPE tumor samples using the QiaAmp þ þ Patients with advanced ROS1 or ALK NSCLC were con- FFPE DNA isolation kit from Qiagen (29). Samples were PCR fi – ALK sidered for rebiopsy following progression on specificROS1or ampli ed using custom primer sets from exons 21 25 of and – ROS1 ALK TKI therapy. All patients gave informed consent for col- exons 36 42 of and directly sequenced using the ABI Big lection of clinical correlates, tissue collection, research testing, Dye Thermocycle Sequencing kit and analyzed on an ABI 3730 and cell line derivation under Institutional Review Board (IRB)- DNA Sequencer (37). Mutation analysis was performed with the approved protocols. Formalin-fixed paraffin-embedded (FFPE), Mutation Surveyor software v3.97-4.0.0 from Soft Genetic. The ROS1 ALK frozen (placed in liquid nitrogen), and/or fresh tissue samples reference sequence used for was NM 002944.2, for EML4 were obtained according to the safety standards of the inter- NM_004304.4, and for NM_019063.3. Anchored-multi- ventional radiologist, pulmonologist, or surgeon. Prior thera- plex PCR (Archer FusionPlex assay) was utilized in three tumor ALK pies and days until progression for each patient were obtained samples to further characterize fusions, but also detected from chart review. Days until progression were determined on other gene fusions. the basis of imaging studies, which demonstrated definitive The SNaPshot assay for evaluation of multiple oncogenic APC, AKT1, BRAF, CTNNB1, EGFR, FLT3, JAK2, growth of a known tumor site or new extra-CNS metastatic mutations in KIT, KRAS, MAP2K1 MEK1 NOTCH1, NRAS, PIK3CA, PTEN deposits. If questionable, serial scans were evaluated to confirm ( ), , TP53 fi continued growth. Patient studies were conducted according and was performed by ampli cation using 13 multiplexed to the Declaration of Helsinki, the Belmont Report, and the PCR reactions followed by single nucleotide base extension reac- U.S.
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