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PINK1 C-terminal domain polypeptide and methods using the same in cancer treatment

A domain, cancer technology, applied to the C-terminal domain of PINK1 in cancer, in the field of cancer treatment, can solve problems such as drug resistance

Inactive Publication Date: 2018-07-17
胡文聪 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The identification of EGFR mutations and the development of EGFR-TKIs are cutting-edge breakthroughs in the treatment of lung cancer, but drug resistance is still an unsolved problem

Method used

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  • PINK1 C-terminal domain polypeptide and methods using the same in cancer treatment
  • PINK1 C-terminal domain polypeptide and methods using the same in cancer treatment
  • PINK1 C-terminal domain polypeptide and methods using the same in cancer treatment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1: Interaction of PINK1 and EGFR in lung adenocarcinoma

[0071] To determine whether PINK1 interacts with EGFR in lung adenocarcinoma, endogenous PINK1 and EGFR were first examined by immunoblot analysis in four lung adenocarcinoma cell lines bearing different types of EGFR: CL1-5 (wild type), PC9(Ex19Del), H1975(L858R+T790M) and H3255(L858R)( Figure 1A ). Subsequently, total cell lysates were subjected to immunoprecipitation analysis with EGFR monoclonal antibody and immunoblot analysis with PINK1 antibody. The results showed that PINK1 was detected in all four immunoprecipitates, indicating the formation of endogenous protein complexes ( Figure 1B ). To visualize the interaction of PINK1 with EGFR proteins, wild-type EGFR-GFP was co-overexpressed with PINK1-myc in CL1-5 cells. The results showed that these two proteins were co-localized in CL1-5 cells, and most of the co-localization occurred just below the plasma membrane ( Figure 1C ). These data s...

Embodiment 2

[0072] Example 2. Inhibition of EGFR dimerization and internalization by PINK1

[0073] Since there may be an interaction between PINK1 and EGFR, the potential role of PINK1 in EGFR was next investigated. When PINK1 was knocked out in CL1-5, PC9, H1975 and H3255 cells, the total EGFR protein was found to decrease, while the expression of EGFR mRNA was not synchronously down-regulated ( Figure 2A , 2B and 2C). A decrease in protein levels without a concomitant decrease in mRNA expression suggests an increase in protein turnover. Based on current knowledge, EGFR turnover is mediated by receptor dimerization and internalization (A.V.Vieira, C.Lamaze, S.L.Schmid.Science.274, 2086-2089 (1996); R.Heukers et al.J. Cell . Sci. 126, 4900-4912 (2013); and A. Tomas, C.E. Futter, E.R. Trends. Cell. Biol. 24, 26-34 (2014)). Therefore, it was investigated whether PINK1 plays a role in these processes. To assess changes in EGFR dimerization under PINK1 manipulation, a lysosomal inhibit...

Embodiment 3

[0075] Example 3. Direct interaction of PINK1-CTD with EGFR-TKD

[0076] To dissect the interaction of PINK1 with EGFR, it was subsequently investigated whether these two protein kinases interact directly and via their interacting domains. Construction of marker-fused full-length EGFR based on different functional EGFR domains (amino acids 1 to 378, 1 to 621, 1 to 644, 1 to 690, 1 to 954, 645 to 1210, 645 to 954, 955 to 1210) Construct, EGFR-marker (amino acids 1 to 1210) and 8 progressively truncated EGFR-marker constructs ( Figure 3A ). Each of these nine constructs was co-overexpressed with full-length PINK1 in HEK293 cells. Cell lysates were analyzed by immunoprecipitation with anti-Flag antibody and immunoprecipitates were analyzed by immunoblot with PINK1 antibody. The data showed that only the full-length EGFR-tagged construct and constructs containing amino acids 1 to 954, 645 to 1210, and 655 to 954 interacted with PINK1, suggesting that EGFR-TKD is a region impor...

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Abstract

The present disclosure includes a PINK1-C-terminal domain (PINK1-CTD) polypeptide that binds to ERBB tyrosine kinase domain (ERBB-TKD) and therefore impedes ERBB from dimerization and activation. ThePINK1-CTD polypeptide inhibits, prevents and / or treats ERBB-expressing cancers. The disclosure demonstrates the anti-tumor function of the PINK1-CTD, which provides a new direction for ERBB-expressingcancer therapy.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application US 62 / 155,520, filed May 1, 2015, which is hereby incorporated by reference in its entirety. technical field [0003] The present disclosure relates to polypeptides useful in the treatment of cancer and methods of using the polypeptides to treat cancer. More particularly, the present disclosure relates to the PINK1 C-terminal domain (PINK1-CTD) for use in the treatment of ERBB-expressing cancers. Background technique [0004] In 2004, the identification of activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain (TKD) ushered in a new era in the treatment of lung cancer. Mutated EGFR functions as a driver gene for lung cancer carcinogenesis in 50% of Asian lung adenocarcinoma patients and 10% of Caucasian lung adenocarcinoma patients. Unlike the traditional ligand-dependent activation of wild-type EGFR, EGFR mutants are c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/00C07K14/71C07K19/00A61K38/16A61K39/395A61P35/00
CPCA61K39/395C07K14/71C07K14/00C12Y207/11001C07K2319/10C07K2319/41C07K2319/43A61K38/179A61K31/517A61K31/5377A61K45/06C12N9/12A61P35/00A61K38/45A61K2300/00
Inventor 杨泮池林佩莹黄舶沧
Owner 胡文聪
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