Anaplastic lymphoma kinase (ALK) 1 and the related leukocyte tyrosine kinase (LTK) 2 are recently deorphanized receptor tyrosine kinases (RTK) 3 . Together with their activating cytokines, ALKAL1 and ALKAL2 (also called FAM150A/FAM150B and AUGβ/AUGα) 4-6 , they are involved in neural development 7 , cancer [7][8][9] , and autoimmune diseases 10 . Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain 11 , consistent with a metabolic role in Drosphila 12 . Despite such functional pleiotropy and growing therapeutic relevance 13,14 , structural insights into ALK and LTK and their complexes with cognate cytokines had remained elusive. Here, we show that the cytokine-binding segments of human ALK and LTK comprise an unprecedented architectural chimera of a permuted TNF-like module that braces a Glycine-rich subdomain featuring a hexagonal lattice of long polyglycine-II helices. The cognate cytokines ALKAL1 and ALKAL2 are monomeric three-helix bundles, yet their binding to ALK and LTK elicit similar dimeric assemblies with twofold 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 diverse structure-function findings, we propose a structural and mechanistic blueprint for complexes of ALK family receptors, thereby extending the repertoire of ligand-mediated dimerization mechanisms adopted by RTK. MainALK is an evolutionarily ancient RTK with the vertebrate orthologues uniquely endowed with an Nterminal heparin binding domain (HBD) (Fig. 1a and Extended Data Fig. 1a,b). Gene duplication in vertebrates spawned LTK as a second ALK-like receptor 16 , which evolved divergently with loss of the HBD and additionally the MAM-LDLa-MAM module in mammals (Extended Data Fig. 1c). The common architectural hallmark in the ectodomains of ALK and LTK comprises their cytokine-binding segment, which is unique among cytokine receptors and features an intriguing array of a TNF-like (TNFL) module, a glycine-rich (GR) region, and a membrane-proximal EGF-like module (EGFL) (Fig. 1a). Whereas ALKAL1 and ALKAL2 are both strong activators of LTK 4 , only ALKAL2 potently activates ALK 5,6 coupled to additional regulation via glycosaminoglycan binding to its HBD 15 .
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.
RNA therapeutics represent a promising class of drugs and some of the successful therapeutics have been recently transformed into clinics for several disorders. A growing body of evidence has underlined the involvement of aberrant expression of cancer-associate genes or RNA splicing in the pathogenesis of a variety of cancers. In addition, there have been >200 clinical trials of oligonucleotide therapeutics targeting a variety of molecules in cancers. Although there are no approved RNA therapeutics against cancers so far, some promising outcomes have been obtained in phase 1/2 clinical trials. We will review the recent advances in the study of cancer pathogenesis associated with RNA therapeutics and the development of RNA therapeutics for cancers.
e13019 Background: Since trastuzumab emtansine (T-DM1) was established as a standard treatment option, the treatment strategy of metastatic HER2-positive breast cancer has markedly changed. However, clinical evidence regarding the treatments beyond T-DM1 is insufficient. In this study, we attempted to describe real-world selection and efficacy of treatments following T-DM1 for metastatic HER2-positive breast cancer. Methods: This multi-center retrospective cohort study was conducted in 17 hospitals in Japan. Consecutive patients with metastatic HER2-positive breast cancer who had received T-DM1 and started post-T-DM1 treatments between January 2014 and December 2018 were enrolled. Patients treated with investigational drugs were excluded. The primary endpoint was objective response rate (ORR) of post-T-DM1 treatments. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS). Results: In this study, 325 patients were eligible, of which 182 (56.0%) cases were estrogen receptor-positive and 61 (18.8%) had brain metastases. T-DM1 had been used as the first to 11th (median third) line treatment for metastatic disease. The types of post-T-DM1 treatment were as follows: 1) chemotherapy concomitant with trastuzumab and pertuzumab (n = 102; 31.4%), 2) chemotherapy concomitant with trastuzumab only (n = 78; 24.0%), 3) lapatinib with capecitabine (n = 63; 19.4%), and 4) others (n = 82; 25.2%). ORR of post-T-DM1 treatments was 22.8% (95% confidence interval [CI]: 18.1 to 28.0) and DCR was 66.6% (95% CI: 60.8 to 72.0), calculated with 290 eligible cases with the target lesion. Median PFS was 6.1 months (95%CI: 5.3 to 6.7), median TTF was 5.1 months (95%CI: 4.4 to 5.6), and median OS was 23.7 months (95%CI: 20.7 to 27.4). Conclusions: This real-world study showed that post-T-DM1 treatments had modest anti-tumor activity. Development of more effective treatments beyond T-DM1 is needed for metastatic HER2-positive breast cancer. Clinical trial information: UMIN000037747 .
A64-year-oldwomanwasreferredtoourhospitalwithapalpablemassinherleftbreast.Mammog-raphyandultrasonographyshoweda40-mm,well-circumscribedmasswithaxillarylymphadenopathy.A coreneedlebiopsyofthemasswasdone,whichwasdiagnosedasadenocarcinoma.PET-CTscanshowed alarge,80-mmmasswithabnormalFDGaccumulationintheileocecalregion,andlowerendoscopywas performed.Acircumferentialprotuberantlesionwasfoundintheascendingcolon,andthediagnosisof adenocarcinomawasconfirmedbybiopsy.Thediagnosisofascendingcoloncancerwithbreastandaxillarylymphnodemetastases,cT2N1M1b,cStageIVb,wasfirstconsideredbasedontheimagingandpathologicalfindings,butoverlappingcancerscouldnotberuledout.Partialmastectomy,axillarylymphnode dissection, laparoscopic right hemicolectomy, and D3 lymph node dissection were performed due to the rapid growth of the breast lesion. Based on the surgical pathology, she was diagnosed with advanced colorectalcancerwithbreastmetastasis.Sincesolitarybreastmetastasesareextremelyrareasdistant metastasesincolorectalcancer,thiscaseisreportedalongwithaliteraturereview.
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