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Adaptive Resistance Mechanisms in EGFR Mutant NSCLC
Published in Il-Jin Kim, Companion Diagnostics (CDx) in Precision Medicine, 2019
Mariacarmela Santarpia, Niki Karachaliou, Martyna Filipska, Clara Mayo-de-las-Casas, Chiara Lazzari, Maria González-Cao, Rafael Rosell
In a recent work by our group, we demonstrated that lung cancer cells survive initial EGFR inhibitor treatment through activation of, not only STAT3, but also Src-YAP1 signaling, and co-targeting EGFR, STAT3, and Src was synergistic in two EGFR-mutant NSCLC cell lines. High expression of STAT3 or YAP1 predicted worse PFS in two distinct cohorts of EGFR-mutant NSCLC patients treated with first-line EGFR TKIs (Chaib et al., 2017). Co-targeting EGFR, STAT3 and Src-YAP1 with a triple combination was highly synergistic in vitro and in vivo. We have now extended our work to discover that STAT3 but mainly Src-YAP1 are regulatory nodes for the expression of RTKs and non-RTKs. RTKs and non-RTKs are commonly expressed in NSCLC (Rikova et al., 2007). With genetic and pharmacological inhibition, we found that Src family kinases and YAP1 are controlling the expression of RTKs AXL and MET as well as the transmembrane protein CUB-domain containing protein 1 (CDCP1) (Karachaliou et al., 2018). Both AXL and CDCP1 expression were negative predictive factors for treatment with single EGFR TKIs. The combination of gefitinib or osimertinib with a JAK/FAK/Src inhibitor TPX-0005, currently in a phase I/II clinical trial, was synergistic in culture and in xenograft models. We are on the verge of starting a phase I/II study with the combination of osimertinib with TPX-0005 as first-line therapy for metastatic, EGFR mutant NSCLC patients.
Inherited ADAMTS13 mutations associated with Thrombotic Thrombocytopenic Purpura: a short review and update
Published in Platelets, 2023
Zoe Markham-Lee, Neil V. Morgan, Jonas Emsley
There are 2 CUB domains at the C-terminus, unique to ADAMTS13 within the ADAMTS family. The CUB domains are involved in the initial binding between ADAMTS13 and the D4CK domain of VWF. This results in conformational changes in both proteins, resulting in linearizing VWF and unfolding of ADAMTS13 through disruption of the Spacer–CUB interaction [26]. Previous work has revealed that ADAMTS13 folds its distal CUB domains to the proximal spacer domain to limit exposure of the N-terminal exosites until required for interaction with VWF [13]. Mutations in both CUB1–2 affect protein secretion rather than protease activity directly. Mutation p.G1239V (c. 3716G>T) affecting CUB-1 was reported in a homozygous patient with reduced plasma ADAMTS13 levels and recurring relapse [29,30]. E1382Rfs6 (c. 4143dupA) in CUB2 causes loss of 49 AAs with subsequent negligible secretion and protease activity. There is association with neonatal-childhood onset TTP [31].
Fast-tracking antibody maturation using a B cell-based display system
Published in mAbs, 2022
Hitomi Masuda, Atsushi Sawada, Shu-ichi Hashimoto, Kanako Tamai, Ke-Yi Lin, Naoto Harigai, Kohei Kurosawa, Kunihiro Ohta, Hidetaka Seo, Hiroshi Itou
With the successful verification of the ADLib® KI-AMP using three anti-hVEGF-A hIgG1 sequences as a model case, we aimed to extend its applicability to a potential therapeutic antibody candidate obtained using the conventional hybridoma method to further improve its affinity. We focused on in-house established mouse monoclonal antibodies against human CUB domain containing protein 1 (hCDCP1), a novel therapeutic target against cancer.38 One anti-hCDCP1 antibody, 12A041, exhibited moderate antigen-binding activity (KD < 10−7 nM, Table 1). The V gene of 12A041 was cloned into the knock-in vector and introduced into the ADLib® KI-AMP cells (Figure S7A). As 12A041 originated from mouse, the resulting cells express mouse-human chimeric antibodies. The hCDCP1/human IgG Fc-positive DT40 clone was isolated using FACS and specific binding to recombinant hCDCP1 of secreted antibodies was confirmed using ELISA (Figure S7B).
New insights into the role of co-receptor neuropilins in tumour angiogenesis and lymphangiogenesis and targeted therapy strategies
Published in Journal of Drug Targeting, 2021
Lin Zhao, Hongyuan Chen, Lu Lu, Lei Wang, Xinke Zhang, Xiuli Guo
NRP1 and NRP2 share a common basic domain structure, including a large N-terminal extracellular domain consisting of 860 amino acids, a short single transmembrane domain consisting of 23 amino acids, and a short small cytoplasmic domain (44 amino acids in NRP1 and 43 amino acids in NRP2) [25]. The extracellular region of NRPs is divided into five domains, termed as a1, a2 (complement protein C1r/C1s, Uegf, and Bmp1, CUB) domains, b1, b2 (tandem factor V/VIII homology) domains and c (meprin, A-5 protein, and protein tyrosine phosphatase μ, MAM) domain. It is currently clear that the a1, a2 domains contain approximately 220 amino acids and deletion analysis of the domain, which indicates that the a1, a2 domain are involved in the binding of semaphorin [26]. The b1 and b2 domains contain about 150 amino acids and are essential for VEGF binding [27]. The c domain contains about 170 amino acids and may act as an insulator, shielding the rest of the extracellular domain from the membrane environment and positioning other domains (a1, a2 and b1, b2) for their interaction with their corresponding co-receptors [28]. In addition, both NRP1 and NRP2a have a short catalytically inactive cytoplasmic domain. The cytoplasmic domain contains a C-terminal SEA (serine-glutamine-alanine) motif that interacts with intracellular proteins containing the PSD-95/Dlg/ZO-1 (PDZ)-domain, such as Synectin, an endocytic transport regulator [29,30].