New crossroads for potential therapeutic intervention in cancer - intersections between CDCP1, EGFR family members and downstream signaling pathways

Abstract

Signaling pathways regulated by the receptor CDCP1 play central roles in promoting cancer and in mediating resistance to chemo-and targeted-therapies. In this perspective we briefly summarize these findings as well as data demonstrating poorer outcomes for several malignancies that exhibit elevated CDCP1 expression. Promising data from preclinical studies suggest that CDCP1 targeted agents, including therapeutic antibodies, could be useful in the treatment of cancer patients selected on the basis of activation of CDCP1 and its signaling partners including EGFR, HER2, Met and Src.

CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo

“…CUB domain-containing protein 1 (CDCP1), also known as SIMA135 (15), gp140 (16), CD318 (17), or Trask (18), is a transmembrane protein that is frequently overexpressed in a variety of human cancers (19)(20)(21). Several papers demonstrate that CDCP1 is a potent oncogene that drives cancer development, invasion,…”

Substrate-biased activity-based probes identify the urokinase-plasminogen axis as a master regulator of metastatic signaling by orphan membrane receptor CDCP1

“…The present work also contributes significantly to delineating the importance of the CDCP1 cleavage axis in progression of a growing list of malignancies including ovarian 34,54,55 , breast 47 , prostate 35 , colorectal 43 and pancreatic 42,45 cancer. Our results support previous studies indicating the role of uPA 40 and plasmin 35,56 in CDCP1 proteolysis and extend these results by establishing this proteolytic axis in CDCP1-mediated cancer progression using diseaserelevant models and patient samples.…”

“…CUB Domain-Containing Protein 1 (CDCP1) is a single pass transmembrane receptor 34 which promotes oncogenic signaling in cooperation with receptors [34][35][36][37][38] including EGFR, HER2 and β1 integrin. Extracellular CDCP1 proteolysis which is essential for pro-metastatic signaling converts full-length (FL) 135 kDa CDCP1 to a 70 kDa transmembrane carboxyl-terminal fragment (CTF) and a 65 kDa amino-terminal fragment (ATF) that is either shed from the cell surface [39][40][41] or remains tethered to CDCP1-FL/-CTF 42 , potentially allowing paracrine, autocrine and/or juxtracrine signaling (Fig.…”

“…In preclinical models CDCP1 proteolysis promotes vascular metastasis of prostate cancer 35 and CDCP1 homodimerization-induced cell migration in triple-negative breast cancer 47 . Various proteases have been suggested to regulate CDCP1 cleavage 34,40,41 , and while plasmin is known to play an important role in CDCP1 prometastatic functions 35 the proteases directly regulating oncogenic CDCP1 cleavage remain unknown.…”

2D-QSAR and 3D-QSAR Analyses for EGFR Inhibitors

“…EGFR is activated by its cognate ligands via forming a homodimer or heterodimer with other members of the EGFR family, such as epidermal growth factor (EGF) and transforming growth factor alpha (TGF- α ) [ 1 ]. Several signal transduction cascades are initiated when EGFR is activated and then lead to DNA synthesis and cell proliferation [ 2 , 3 ]. While EGFR is amplified or mutated, DNA synthesis and cell proliferation will be abnormal and lead to cancer.…”