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1.
Clin Cancer Res ; 27(10): 2899-2909, 2021 05 15.
Article in English | MEDLINE | ID: mdl-33685866

ABSTRACT

PURPOSE: Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion (ROS1)-positive (ROS1+) non-small cell lung cancer (NSCLC) is crizotinib or entrectinib. Lorlatinib, a next-generation anaplastic lymphoma kinase/ROS1 inhibitor, recently demonstrated efficacy in ROS1+ NSCLC, including in crizotinib-pretreated patients. However, mechanisms of lorlatinib resistance in ROS1+ disease remain poorly understood. Here, we assessed mechanisms of resistance to crizotinib and lorlatinib. EXPERIMENTAL DESIGN: Biopsies from patients with ROS1 + NSCLC progressing on crizotinib or lorlatinib were profiled by genetic sequencing. RESULTS: From 55 patients, 47 post-crizotinib and 32 post-lorlatinib biopsies were assessed. Among 42 post-crizotinib and 28 post-lorlatinib biopsies analyzed at distinct timepoints, ROS1 mutations were identified in 38% and 46%, respectively. ROS1 G2032R was the most commonly occurring mutation in approximately one third of cases. Additional ROS1 mutations included D2033N (2.4%) and S1986F (2.4%) post-crizotinib and L2086F (3.6%), G2032R/L2086F (3.6%), G2032R/S1986F/L2086F (3.6%), and S1986F/L2000V (3.6%) post-lorlatinib. Structural modeling predicted ROS1L2086F causes steric interference to lorlatinib, crizotinib, and entrectinib, while it may accommodate cabozantinib. In Ba/F3 models, ROS1L2086F, ROS1G2032R/L2086F, and ROS1S1986F/G2032R/L2086F were refractory to lorlatinib but sensitive to cabozantinib. A patient with disease progression on crizotinib and lorlatinib and ROS1 L2086F received cabozantinib for nearly 11 months with disease control. Among lorlatinib-resistant biopsies, we also identified MET amplification (4%), KRAS G12C (4%), KRAS amplification (4%), NRAS mutation (4%), and MAP2K1 mutation (4%). CONCLUSIONS: ROS1 mutations mediate resistance to crizotinib and lorlatinib in more than one third of cases, underscoring the importance of developing next-generation ROS1 inhibitors with potency against these mutations, including G2032R and L2086F. Continued efforts are needed to elucidate ROS1-independent resistance mechanisms.


Subject(s)
Aminopyridines/pharmacology , Crizotinib/pharmacology , Drug Resistance, Neoplasm/genetics , Lactams/pharmacology , Lung Neoplasms/genetics , Oncogene Proteins, Fusion/genetics , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins/genetics , Pyrazoles/pharmacology , Adult , Aged , Aged, 80 and over , Alleles , Amino Acid Substitution , Aminopyridines/chemistry , Aminopyridines/therapeutic use , Antigens, Differentiation, B-Lymphocyte/genetics , Biopsy , Cell Line, Tumor , Crizotinib/chemistry , Crizotinib/therapeutic use , Female , Histocompatibility Antigens Class II/genetics , Humans , Lactams/chemistry , Lactams/therapeutic use , Lung Neoplasms/diagnosis , Lung Neoplasms/drug therapy , Male , Middle Aged , Models, Molecular , Mutation , Oncogene Proteins, Fusion/chemistry , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/chemistry , Proto-Oncogene Proteins/chemistry , Pyrazoles/chemistry , Pyrazoles/therapeutic use , Structure-Activity Relationship , Young Adult
2.
Clin Cancer Res ; 26(11): 2535-2545, 2020 06 01.
Article in English | MEDLINE | ID: mdl-32086345

ABSTRACT

PURPOSE: Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed. EXPERIMENTAL DESIGN: We performed FISH and/or next-generation sequencing on 207 posttreatment tissue (n = 101) or plasma (n = 106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance. RESULTS: MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib (P = 0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid responses to ALK/MET combination therapy. CONCLUSIONS: Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET.


Subject(s)
Anaplastic Lymphoma Kinase/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Drug Resistance, Neoplasm/genetics , Gene Amplification , Lung Neoplasms/genetics , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/genetics , Aminopyridines , Anaplastic Lymphoma Kinase/genetics , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Crizotinib/pharmacology , Gene Expression Regulation, Neoplastic , High-Throughput Nucleotide Sequencing , Humans , Lactams , Lactams, Macrocyclic/pharmacology , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Prognosis , Pyrazoles , Tumor Cells, Cultured
3.
Cancer Discov ; 8(6): 714-729, 2018 06.
Article in English | MEDLINE | ID: mdl-29650534

ABSTRACT

The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK. Under comparable conditions, N-ethyl-N-nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single ALK mutations. In similar screens with EML4-ALK containing single ALK resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound ALK mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound ALK mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of ALK mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound ALK mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies.Significance: Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound ALK mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance. Cancer Discov; 8(6); 714-29. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663.


Subject(s)
Anaplastic Lymphoma Kinase/genetics , Drug Resistance, Neoplasm , Lactams, Macrocyclic/administration & dosage , Lung Neoplasms/genetics , Mutation , Aminopyridines , Animals , Cell Line, Tumor , Crizotinib/administration & dosage , Crizotinib/pharmacology , Ethylnitrosourea/adverse effects , Female , Humans , Lactams , Lactams, Macrocyclic/pharmacology , Lung Neoplasms/chemically induced , Lung Neoplasms/drug therapy , Mice , Oncogene Proteins, Fusion/genetics , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Pyrazoles , Exome Sequencing , Xenograft Model Antitumor Assays
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