ABSTRACT
Anaplastic lymphoma kinase (ALK)1 and the related leukocyte tyrosine kinase (LTK)2 are recently deorphanized receptor tyrosine kinases3. Together with their activating cytokines, ALKAL1 and ALKAL24-6 (also called FAM150A and FAM150B or AUGß and AUGα, respectively), they are involved in neural development7, cancer7-9 and autoimmune diseases10. Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain11, consistent with a metabolic role for Drosophila ALK12. Despite such functional pleiotropy and growing therapeutic relevance13,14, structural insights into ALK and LTK and their complexes with cognate cytokines have remained scarce. Here we show that the cytokine-binding segments of human ALK and LTK comprise a novel architectural chimera of a permuted TNF-like module that braces a glycine-rich subdomain featuring a hexagonal lattice of long polyglycine type II helices. The cognate cytokines ALKAL1 and ALKAL2 are monomeric three-helix bundles, yet their binding to ALK and LTK elicits similar dimeric assemblies with two-fold symmetry, that tent a single cytokine molecule proximal to the cell membrane. We show that the membrane-proximal EGF-like domain dictates the apparent cytokine preference of ALK. Assisted by these diverse structure-function findings, we propose a structural and mechanistic blueprint for complexes of ALK family receptors, and thereby extend the repertoire of ligand-mediated dimerization mechanisms adopted by receptor tyrosine kinases.
Subject(s)
Anaplastic Lymphoma Kinase/chemistry , Anaplastic Lymphoma Kinase/metabolism , Cytokines/chemistry , Cytokines/metabolism , Receptor Protein-Tyrosine Kinases/chemistry , Receptor Protein-Tyrosine Kinases/metabolism , Anaplastic Lymphoma Kinase/classification , Anaplastic Lymphoma Kinase/genetics , Binding Sites , Enzyme Activation , Epidermal Growth Factor/chemistry , Glycine , HEK293 Cells , Humans , Models, Molecular , Multiprotein Complexes/chemistry , Multiprotein Complexes/metabolism , Mutation , Protein Binding , Protein Domains , Protein Multimerization , Substrate SpecificityABSTRACT
BACKGROUND: Trastuzumab emtansine (T-DM1) treatment for human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer after taxane with trastuzumab and pertuzumab is standard therapy. However, treatment strategies beyond T-DM1 are still in development with insufficient evidence of their effectiveness. Here, we aimed to evaluate real-world treatment choice and efficacy of treatments after T-DM1 for HER2-positive metastatic breast cancer. METHODS: In this multi-centre retrospective cohort study involving 17 hospitals, 325 female HER2-positive metastatic breast cancer patients whose post-T-DM1 treatment began between April 15, 2014 and December 31, 2018 were enrolled. The primary end point was the objective response rate (ORR) of post-T-DM1 treatments. Secondary end points included disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS). RESULTS: The median number of prior treatments of post-T-DM1 treatment was four. The types of post-T-DM1 treatments included (1) chemotherapy in combination with trastuzumab and pertuzumab (n = 102; 31.4%), (2) chemotherapy concomitant with trastuzumab (n = 78; 24.0%), (3), lapatinib with capecitabine (n = 63; 19.4%), and (4) others (n = 82; 25.2%). ORR was 22.8% [95% confidence interval (CI): 18.1-28.0], DCR = 66.6% (95% CI 60.8-72.0), median PFS = 6.1 months (95% CI 5.3-6.7), median TTF = 5.1 months (95% CI 4.4-5.6), and median OS = 23.7 months (95% CI 20.7-27.4). CONCLUSION: The benefits of treatments after T-DM1 are limited. Further investigation of new treatment strategies beyond T-DM1 is awaited for HER2-positive metastatic breast cancer patients.
