Potential drug target for tumors: CDCP1
The process of tumor cell infiltration, adhesion and migration is an important research direction in the process of drug development. CUB domain containing protein 1 (CDCP1) is involved in the development of various tumors and is a potential drug target.
CDCP1, also known as CD318, SIMA135, gp140 and TRASK, is a type I single transmembrane glycoprotein containing three CUB domains. CDCP1 is highly expressed in breast cancer, pancreatic cancer, colon cancer, lung cancer and other metastatic tumors. It plays an important role in promoting tumor infiltration and invasion, and is associated with poor prognosis of various cancers.
Figure 1. CDCP1 structure [1].
The CUB1 and CUB2 domains of CDCP1 are easily hydrolyzed by serine-like proteolytic enzymes such as trypsin or serum plasmin to form a 70kDa transmembrane carboxy-terminal fragment (CTF) and a 65kDa amino-terminal fragment (NTF or ATF). This hydrolysis is extremely active in tumor cells. However, hydrolysis of CDCP1 does not always result in the shedding of the CDCP1 ectodomain, which can interact with membrane-bound CDCP1, allowing signal transduction between different CDCP1 fragments. CDCP1 does not depend on its cleavage state to function.
Figure 2. Hydrolysis of CDCP1 [2].
Recent studies have found that CDCP1 can recruit Src kinase to lipid rafts, triggering a cascade reaction, leading to the invasion of cancer cells into the basal layer. The spatial regulation of the cells makes the normal "root tip extrusion" of the cells resist, makes the cancer cells invasive, and promotes the occurrence of carcinogenesis [3]. In addition, CDCP1 can also interact with EGFR, Her2, and β1 integrin to mediate different signaling pathways, further exacerbating the disease.
Figure 3. CDCP1-mediated signaling pathway in cancer [4].
CDCP1 Drug Development
Since the research on the mechanism of CDCP1 is not yet fully understood, it is difficult to define the mode of action of the drug. For example, some antibodies stimulate the phosphorylation of CDCP1 [5]. For therapeutic antibodies, if the transient activation is followed by sustained and obvious target downregulation, then this may also be a viable mode of action. At present, most companies deploying CDCP1 drugs are still in the preclinical research stage, such as RG7287 [6] developed by Roche Glycart AG and 25A11 developed by Alexion, both of which are antibody drugs.
Targeting CDCP1 could include inhibiting CDCP1-CTF or CDCP1-ATF, inhibiting the hydrolysis process of CDCP1, or targeting related signaling pathways. The high expression of CDCP1 in a variety of tumor cells makes it suitable for the development of conjugated drugs. At present, there are many different types of drug explorations, such as antibody drug conjugates (ADC) [7], radionuclide drug conjugates (RDC) [8], and CAR-T [9] therapy. CDCP1 can also be used as a new target for early diagnosis of cancer, either as a tracer target for medical imaging or a body fluid detection marker.
KACTUS has developed a series of high-quality CDCP1 recombinant protein products, which can be applied to different stages of CDCP1-targeted drug discovery, screening and optimization. The products cover a variety of species, different label designs and different functional domains, etc. to meet various experimental needs.
Product Data
Figure 4. Human CDCP1, His Tag captured on CM5 Chip via anti-His antibody can bind Anti-CDCP1 Antibody, hFc Tag with an affinity constant of 0.18nM as determined in SPR assay (Biacore T200).
Figure 5. Anti-CDCP1 Antibody, hFc Tag captured on CM5 Chip via Protein A can bind Biotinylated Mouse CDCP-1, His-Avi Tag with an affinity constant of 0.74 μM as determined in SPR assay (Biacore T200).
Figure 6. Immobilized Human CDCP1, hFc Tag at 2μg/mL (100μL/well) on the plate. Dose response curve for Biotinylated Anti-CDCP1 Antibody, hFc Tag with an EC50 of 15.3ng/mL determined by ELISA.
Figure 7. Immobilized Anti-CDCP1 Antibody, hFc Tag at 1μg/mL (100μL/well) on the plate. Dose response curve for Biotinylated Human CDCP1, His Tag with an EC50 of 64.8ng/mL determined by ELISA.
Product List
References
[1] Qi X, Gao J, Li Z, Zhang G, Li J, Fu Y, Cai M, Wang H, Tong T. CDCP1: A promising diagnostic biomarker and therapeutic target for human cancer. Life Sci. 2022 Jul 15;301:120600. doi: 10.1016/j.lfs.2022.120600. Epub 2022 May 2. PMID: 35504333.
[2] He Y, Wortmann A, Burke LJ, Reid JC, Adams MN, Abdul-Jabbar I, Quigley JP, Leduc R, Kirchhofer D, Hooper JD. Proteolysis-induced N-terminal ectodomain shedding of the integral membrane glycoprotein CUB domain-containing protein 1 (CDCP1) is accompanied by tyrosine phosphorylation of its C-terminal domain and recruitment of Src and PKCdelta. J Biol Chem. 2010 Aug 20;285(34):26162-73. doi: 10.1074/jbc.M109.096453. Epub 2010 Jun 15. PMID: 20551327; PMCID: PMC2924022.
[3] Kajiwara K, Chen PK, Abe Y, Okuda S, Kon S, Adachi J, Tomonaga T, Fujita Y, Okada M. Src activation in lipid rafts confers epithelial cells with invasive potential to escape from apical extrusion during cell competition. Curr Biol. 2022 Aug 22;32(16):3460-3476.e6. doi: 10.1016/j.cub.2022.06.038. Epub 2022 Jul 8. PMID: 35809567.
[4] Qi X, Gao J, Li Z, Zhang G, Li J, Fu Y, Cai M, Wang H, Tong T. CDCP1: A promising diagnostic biomarker and therapeutic target for human cancer. Life Sci. 2022 Jul 15;301:120600. doi: 10.1016/j.lfs.2022.120600. Epub 2022 May 2. PMID: 35504333.
[5] Alvares SM, Dunn CA, Brown TA, Wayner EE, Carter WG. The role of membrane microdomains in transmembrane signaling through the epithelial glycoprotein Gp140/CDCP1. Biochim Biophys Acta. 2008 Mar;1780(3):486-96. doi: 10.1016/j.bbagen.2008.01.010. Epub 2008 Jan 26. PMID: 18269919; PMCID: PMC4975934.
[6] Kollmorgen G, Niederfellner G, Lifke A, Spohn GJ, Rieder N, Harring SV, Bauss F, Burtscher H, Lammers R, Bossenmaier B. Antibody mediated CDCP1 degradation as mode of action for cancer targeted therapy. Mol Oncol. 2013 Dec;7(6):1142-51. doi: 10.1016/j.molonc.2013.08.009. Epub 2013 Sep 3. PMID: 24055141; PMCID: PMC5528444.
[7] Khan T, Lyons NJ, Gough M, Kwah KKX, Cuda TJ, Snell CE, Tse BW, Sokolowski KA, Pearce LA, Adams TE, Rose SE, Puttick S, Pajic M, Adams MN, He Y, Hooper JD, Kryza T. CUB Domain-Containing Protein 1 (CDCP1) is a rational target for the development of imaging tracers and antibody-drug conjugates for cancer detection and therapy. Theranostics. 2022 Oct 3;12(16):6915-6930. doi: 10.7150/thno.78171. PMID: 36276654; PMCID: PMC9576610.
[8] Zhao N, Chopra S, Trepka K, Wang YH, Sakhamuri S, Hooshdaran N, Kim H, Zhou J, Lim SA, Leung KK, Egusa EA, Zhu J, Zhang L, Foye A, Sriram R, Chan E, Seo Y, Feng FY, Small EJ, Chou J, Wells JA, Aggarwal R, Evans MJ. CUB Domain-Containing Protein 1 (CDCP1) Is a Target for Radioligand Therapy in Castration-Resistant Prostate Cancer, including PSMA Null Disease. Clin Cancer Res. 2022 Jul 15;28(14):3066-3075. doi: 10.1158/1078-0432.CCR-21-3858. PMID: 35604681; PMCID: PMC9288514.
[9] Schäfer D, Tomiuk S, Küster LN, Rawashdeh WA, Henze J, Tischler-Höhle G, Agorku DJ, Brauner J, Linnartz C, Lock D, Kaiser A, Herbel C, Eckardt D, Lamorte M, Lenhard D, Schüler J, Ströbel P, Missbach-Guentner J, Pinkert-Leetsch D, Alves F, Bosio A, Hardt O. Identification of CD318, TSPAN8 and CD66c as target candidates for CAR T cell based immunotherapy of pancreatic adenocarcinoma. Nat Commun. 2021 Mar 5;12(1):1453. doi: 10.1038/s41467-021-21774-4. PMID: 33674603; PMCID: PMC7935963.
