Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in ROS1 Fusion–Positive Lung Cancer
| Autor: | Satoshi Yoda, Wafa Malik, Adam Langenbucher, Justin F. Gainor, Sai-Hong Ignatius Ou, Kylie Prutisto-Chang, Ramin Sakhtemani, Jennifer L Peterson, Aaron N. Hata, Alexander Drilon, Andrew Do, Jessica J. Lin, Adam J. Schoenfeld, Viola W. Zhu, Ted William Johnson, Jochen K. Lennerz, Lecia V. Sequist, Noura J. Choudhury, Ibiayi Dagogo-Jack, Subba R. Digumarthy, Christina Falcon, Charlotte E. Lee, Alice T. Shaw, Michael S. Lawrence, Beow Y. Yeap, Jennifer S. Temel, Harper Hubbeling |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Models Molecular 0301 basic medicine Oncology Cancer Research Lung Neoplasms Oncogene Proteins Fusion Biopsy Aminopyridines Entrectinib medicine.disease_cause chemistry.chemical_compound 0302 clinical medicine Anaplastic lymphoma kinase Aged 80 and over Middle Aged Protein-Tyrosine Kinases 030220 oncology & carcinogenesis Female KRAS medicine.drug Adult medicine.medical_specialty Lactams Cabozantinib Article Structure-Activity Relationship Young Adult 03 medical and health sciences Crizotinib Cell Line Tumor Proto-Oncogene Proteins Internal medicine medicine ROS1 Humans Lung cancer Protein Kinase Inhibitors Alleles Aged business.industry Histocompatibility Antigens Class II medicine.disease Lorlatinib Antigens Differentiation B-Lymphocyte 030104 developmental biology Amino Acid Substitution chemistry Drug Resistance Neoplasm Mutation Pyrazoles business |
| Zdroj: | Clin Cancer Res |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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