Discoidin domain receptor 1: New star in cancer-targeted therapy and its complex role in breast carcinoma (Review)

Jing, Hui; Song, Jingyuan; Zheng, Junnian

doi:10.3892/ol.2018.7795

Cited by 28 publications

(31 citation statements)

References 88 publications

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“…DDR1 is a unique member of RTK family and was first identified during a search for tyrosine kinase proteins expressed in human breast carcinoma (Jing et al ., ; Johnson et al ., ). It has been reported that DDR1 is significantly overexpressed in several human tumors.…”

Section: Discussionmentioning

confidence: 97%

Targeting of DDR1 with antibody‐drug conjugates has antitumor effects in a mouse model of colon carcinoma

et al. 2019

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DDR1 has been identified as a cancer‐associated receptor tyrosine kinase that is highly expressed in several malignancies relative to normal tissues. Clinically approved multi‐kinase inhibitors, such as nilotinib, inhibit DDR1‐mediated tumor growth in xenograft models, suggesting DDR1 might be a potential target for cancer treatments. Here, we employed an antibody‐based strategy with a novel anti‐DDR1 antibody‐drug conjugate (ADC) for colon carcinoma treatment. We developed T 4 H 11 ‐DM4, an ADC targeting DDR1 which carries the tubulin inhibitor payload DM4. Immunohistochemical analysis of a tissue microarray containing 100 colon cancer specimens revealed that DDR1 was highly expressed in 81% of tumor tissues. Meanwhile, high expression of DDR1 was associated with poor survival in patients. In vitro , T 4 H 11 ‐DM4 exhibited potent anti‐proliferative activity with half maximal inhibitory concentration (IC 50 ) values in the nanomolar range in a panel of colon cancer cell lines. In vivo , the antitumor efficacy of T 4 H 11 ‐DM4 was evaluated in three colon cancer cell lines expressing different levels of DDR1. T 4 H 11 ‐DM4 achieved complete tumor regression at doses of 5 and 10 mg·kg −1 in HT‐29 and HCT116 tumor models. Moreover, a correlation between in vivo efficacy of T 4 H 11 ‐DM4 and the levels of DDR1 expression on the cell surface was observed. Tumor cell proliferation was caused by the induction of mitotic arrest, indicating that the antitumor effect in vivo was mediated by DM4. In addition, T 4 H 11 ‐DM4 was efficacious in oxaliplatin‐resistant colon cancer models. In exploratory safety studies, T 4 H 11 ‐DM4 exhibited no overt toxicities when multi‐doses were administered at 10 mg·kg −1 into BALB/c nude mice or when a single dose up to 50 mg·kg −1 was administered into BALB/c mice. Overall, our findings highlight the potential of DDR1‐targeted ADC and may facilitate the development of a new effective therapeutic strategy for colon cancer.

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Section: Discussionmentioning

confidence: 97%

Targeting of DDR1 with antibody‐drug conjugates has antitumor effects in a mouse model of colon carcinoma

et al. 2019

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“…These results imply that the OSCC cells might have been addicted to overexpressed DDR1 for their survival. In the same vein, targeting DDR1 alone or in combination with other chemotherapies have been suggested in several neoplasms, including metastatic colorectal cancer, K-RAS driven lung adenocarcinoma, and breast carcinoma [14,[52][53][54].…”

Section: Discussionmentioning

confidence: 99%

Discoidin Domain Receptor-1 (DDR1) is Involved in Angiolymphatic Invasion in Oral Cancer

Chen

Tsai

et al. 2020

Cancers

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The discoidin domain receptor-1 (DDR1) is a non-integrin collagen receptor recently implicated in the collective cell migration of other cancer types. Previously, we identified an elevated expression of DDR1 in oral squamous cell carcinoma (OSCC) cells. Through the data mining of a microarray dataset composed of matched tumor-normal tissues from forty OSCC patients, we distilled overexpressed genes statistically associated with angiolymphatic invasion, including DDR1, COL4A5, COL4A6 and PDPN. Dual immunohistochemical staining further confirmed the spatial locations of DDR1 and PDPN in OSCC tissues indicative of collective cancer cell invasion. An elevated DDR1 expression at both the transcription and protein level was observed by treating keratinocytes with collagen of fibrillar or basement membrane types. In addition, inhibition of DDR1 kinase activity in OSCC TW2.6 cells disrupted cell cohesiveness in a 2D culture, reduced spheroid invasion in a collagen gel matrix, and suppressed angiolymphatic invasion in xenograft tissues. Taken together, these results suggest that collagen deposition in the affected tissues followed by DDR1 overexpression could be central to OSCC tumor growth and angiolymphatic invasion. Thus, DDR1 inhibitors are potential therapeutic compounds in restraining oral cancer, which has not been previously explored.

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“…Accumulating evidence suggests that DDRs are major players in cancer progression in multiple cancer types (Jing, Song, & Zheng, 2018;Rammal et al, 2016;Valiathan et al, 2012). However, there is a paucity of information on the expression and roles of DDRs in melanoma (Cario, 2018).…”

Section: Discussionmentioning

confidence: 99%

Discoidin domain receptors: A promising target in melanoma

Moura

Battistella

Sohail

et al. 2019

Pigment Cell Melanoma Res

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The discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family that signals in response to collagen and that has been implicated in cancer progression. In the present study, we investigated the expression and role of DDR1 in human melanoma progression. Immunohistochemical staining of human melanoma specimens (n = 52) shows high DDR1 expression in melanoma lesions that correlates with poor prognosis. DDR1 expression was associated with the clinical characteristics of Clark level and ulceration and with BRAF mutations. Downregulation of DDR1 by small interfering RNA (siRNA) in vitro inhibited melanoma cells malignant properties, migration, invasion, and survival in several human melanoma cell lines. A DDR tyrosine kinase inhibitor (DDR1‐IN‐1) significantly inhibited melanoma cell proliferation in vitro, and ex vivo and in tumor xenografts, underlining the promising potential of DDR1 inhibition in melanoma.

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Discoidin domain receptor 1: New star in cancer-targeted therapy and its complex role in breast carcinoma (Review)

Cited by 28 publications

References 88 publications

Targeting of DDR1 with antibody‐drug conjugates has antitumor effects in a mouse model of colon carcinoma

Targeting of DDR1 with antibody‐drug conjugates has antitumor effects in a mouse model of colon carcinoma

Discoidin Domain Receptor-1 (DDR1) is Involved in Angiolymphatic Invasion in Oral Cancer

Discoidin domain receptors: A promising target in melanoma

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