Signaling by discoidin domain receptor 1 in cancer metastasis

Gadiya, Mayur; Chakraborty, Goutam

doi:10.1080/19336918.2018.1520556

Cited by 31 publications

(36 citation statements)

References 95 publications

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“…DDR1 is a collagen receptor that mediates cell–microenvironment communication in tumors. Whether anti‐DDR1 ADC can coordinate with checkpoint immunotherapy for tumor deserves further research (Gadiya and Chakraborty, ).…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

et al. 2019

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“…On the contrary, the data presented here suggest that DDR1b-collagen interactions within the lung parenchyma may activate a signalling pathway in HT1080 cells, which eventually inhibits the growth of disseminated cells. In this regard, it will be interesting to examine whether DDR1b expression in HT1080 cells fails to reactivate lung-residing tumour cells from dormancy, as reported in other model 34,142 . Regardless, the current data are consistent with a complex role for DDR1b in metastatic dissemination, which may be cell typeand model-dependent.…”

Section: Discussionmentioning

confidence: 97%

Discoidin Domain Receptors, DDR1b and DDR2, Promote Tumour Growth within Collagen but DDR1b Suppresses Experimental Lung Metastasis in HT1080 Xenografts

Wasinski

Sohail

Bonfil

et al. 2020

Sci Rep

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the Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen. Using an inducible expression system in human HT1080 fibrosarcoma cells, we investigated the role of DDR1b and DDR2 on primary tumour growth and experimental lung metastases. Neither DDR1b nor DDR2 expression altered tumour growth at the primary site. However, implantation of DDR1b-or DDR2-expressing HT1080 cells with collagen I significantly accelerated tumour growth rate, an effect that could not be observed with collagen I in the absence of DDR induction. Interestingly, DDR1b, but not DDR2, completely hindered the ability of HT1080 cells to form lung colonies after intravenous inoculation, suggesting a differential role for DDR1b in primary tumour growth and lung colonization. Analyses of tumour extracts revealed specific alterations in Hippo pathway core components, as a function of DDR and collagen expression, that were associated with stimulation of tumour growth by DDRs and collagen I. Collectively, these findings identified divergent effects of DDRs on primary tumour growth and experimental lung metastasis in the HT1080 xenograft model and highlight the critical role of fibrillar collagen and DDRs in supporting the growth of tumours thriving within a collagen-rich stroma. The DDRs constitute a unique subfamily of receptor tyrosine kinases (RTKs) that signal in response to collagens, and therefore they represent the only RTKs that are directly activated upon contact of cells with their collagenous matrix 1-6. The DDR subfamily comprises two kinases: DDR1 and DDR2 1,2,7. The DDR1 subfamily includes six isoforms generated by alternative splicing, while there is only one form of DDR2. Among the DDR1 isoforms, DDR1a, DDR1b, and DDR1c are full length, highly homologous receptors, with the only structural difference being the presence of 37 additional residues, including two additional tyrosine residues, within the intracellular region of DDR1b and DDR1c, suggesting that these species may activate different downstream signalling pathways 1. DDR1d and DDR1e are truncated, kinase-deficient receptors of unknown function 8. DDR1f contains a full kinase domain but lacks most of the extracellular domains 9. Structurally, the DDRs are type I transmembrane

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“…Indeed, evidence suggests that DDR1 can elicit either tumor-promoting or -suppressing effects on cancer in a context-dependent manner [reviewed in ( 13 )], possibly due to the fact that DDR1 plays a role in the maintenance of normal epithelial integrity by regulating cell–BM and cell–cell interactions ( 14 – 17 ). On the other hand, many studies have shown that overexpression of DDR1 in several cancer types correlates with disease progression ( 18 – 20 ). However, it is important to note that expression analyses in tissue samples are limited because a pro-malignant role for any gene cannot be asserted without functional studies.…”

Section: Ddr1 a Worse Prognostic Biomarker And An Emerging Targetmentioning

confidence: 99%

Discoidin Domain Receptors in Melanoma: Potential Therapeutic Targets to Overcome MAPK Inhibitor Resistance

et al. 2020

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Melanoma is a highly malignant skin cancer with high propensity to metastasize and develop drug resistance, making it a difficult cancer to treat. Current therapies targeting BRAF (V600) mutations are initially effective, but eventually tumors overcome drug sensitivity and reoccur. This process is accomplished in part by reactivating alternate signaling networks that reinstate melanoma proliferative and survival capacity, mostly through reprogramming of receptor tyrosine kinase (RTK) signaling. Evidence indicates that the discoidin domain receptors (DDRs), a set of RTKs that signal in response to collagen, are part of the kinome network that confer drug resistance. We previously reported that DDR1 is expressed in melanomas, where it can promote tumor malignancy in mouse models of melanoma, and thus, DDR1 could be a promising target to overcome drug resistance. In this review, we summarize the current knowledge on DDRs in melanoma and their implication for therapy, with emphasis in resistance to MAPK inhibitors.

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Signaling by discoidin domain receptor 1 in cancer metastasis

Cited by 31 publications

References 95 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 Receptors, DDR1b and DDR2, Promote Tumour Growth within Collagen but DDR1b Suppresses Experimental Lung Metastasis in HT1080 Xenografts

Discoidin Domain Receptors in Melanoma: Potential Therapeutic Targets to Overcome MAPK Inhibitor Resistance

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