The DOI matches its Crossref record; 59 of the 61 references it cites were found in a registry or an index.
Inhibition of Discoidin Domain Receptor 1 Reduces Collagen-mediated Tumorigenicity in Pancreatic Ductal Adenocarcinoma
Open accessPublished version of a preprint
Abstract
The extracellular matrix (ECM), a principal component of pancreatic ductal adenocarcinoma (PDA), is rich in fibrillar collagens that facilitate tumor cell survival and chemoresistance. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that specifically binds fibrillar collagens and has been implicated in promoting cell proliferation, migration, adhesion, ECM remodeling, and response to growth factors. We found that collagen-induced activation of DDR1 stimulated protumorigenic signaling through protein tyrosine kinase 2 (PYK2) and pseudopodium-enriched atypical kinase 1 (PEAK1) in pancreatic cancer cells. Pharmacologic inhibition of DDR1 with an ATP-competitive orally available small-molecule kinase inhibitor (7rh) abrogated collagen-induced DDR1 signaling in pancreatic tumor cells and consequently reduced colony formation and migration. Furthermore, the inhibition of DDR1 with 7rh showed striking efficacy in combination with chemotherapy in orthotopic xenografts and autochthonous pancreatic tumors where it significantly reduced DDR1 activation and downstream signaling, reduced primary tumor burden, and improved chemoresponse. These data demonstrate that targeting collagen signaling in conjunction with conventional cytotoxic chemotherapy has the potential to improve outcome for pancreatic cancer patients. Mol Cancer Ther; 16(11); 2473–85. ©2017 AACR.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“PDAC cells produce “tonic” (low) levels of a distinct oncogenic homo-trimeric collagen that binds to α3β1 integrin, thereby mediating immune suppression and reprogramming the tumor-associated microbiome167”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [167]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
1 retracted
DDR1 Receptor Tyrosine Kinase Promotes Prosurvival Pathway through Notch1 Activation
Kim, H.-G., Hwang, S.-Y., Aaronson, S. A., Mandinova, A., & Lee, S. W. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.236612 · Cited by 94 · cited 1×
“DDR1 inhibition has also been shown to reduce tumorigenicity in multiple tumor models (23, 25, 51, 52).”
BackgroundRetractedKalluri, R., & Zeisberg, M. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1877 · Cited by 4,538 · cited 1×
“Collagen is expressed in PDA by stromal cells, mainly fibroblasts, with a relatively minor but functionally relevant contribution by tumor cells (18, 19).”
BackgroundSomatic mutations affect key pathways in lung adenocarcinoma
Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D. M., Morgan, M. B., et al. (2008) · Nature · doi:10.1038/nature07423 · Cited by 2,681 · cited 1×
“Dasatinib in particular has demonstrated promising therapeutic efficacy in lung cancer cells (57) and squamous cell carcinoma patients (58) harboring gain-of-function DDR2 mutations.”
BackgroundHingorani, S. R., Wang, L., Multani, A. S., Combs, C., Deramaudt, T. B., Hruban, R. H., Rustgi, A. K., Chang, S., & Tuveson, D. A. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.023 · Cited by 2,609
Collagen density promotes mammary tumor initiation and progression
Provenzano, P. P., Inman, D. R., Eliceiri, K. W., Knittel, J. G., Yan, L., Rueden, C., White, J. G., & Keely, P. J. (2008) · BMC Medicine · doi:10.1186/1741-7015-6-11 · Cited by 1,394
Hoff, D. D. V., Ramanathan, R. K., Borad, M. J., Laheru, D. A., Smith, L. S., Wood, T. E., Korn, R. L., Desai, N. P., Trieu, V. N., Iglesias, J. L. M., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.36.5742 · Cited by 1,040 · cited 1×
“In addition, it was reported that the restoration of SPARC expression enhanced radiosensitivity and chemosensitivity in preclinical models of colon cancer (45) and that SPARC expression enhanced chemoresponse in cancer patients (46, 47).”
BackgroundChauhan, V. P., Martin, J. D., Liu, H., Lacorre, D. A., Jain, S. R., Kozin, S. V., Stylianopoulos, T., Mousa, A. S., Han, X., Adstamongkonkul, P., et al. (2013) · Nature Communications · doi:10.1038/ncomms3516 · Cited by 1,031 · cited 1×
“These data support the premise that collagen-mediated activation of DDR1 induces a signal pathway that includes PEAK1, SRC, and PYK2, which in turn are potentially responsible for collagen-induced chemoresistance (3, 39) and tumor progression.”
BackgroundThe Discoidin Domain Receptor Tyrosine Kinases Are Activated by Collagen
Vogel, W., Gish, G. D., Alves, F., & Pawson, T. (1997) · Molecular Cell · doi:10.1016/s1097-2765(00)80003-9 · Cited by 1,002 · cited 1×
“The DDR family includes DDR1 and DDR2, which are closely related collagen-specific receptor tyrosine kinases (RTK) that recognize and bind several types of collagen (5-7).”
BackgroundKadler, K. E., Baldock, C., Bella, J., & Boot-Handford, R. (2007) · Journal of Cell Science · doi:10.1242/jcs.03453 · Cited by 887 · cited 1×
“The DDR family includes DDR1 and DDR2, which are closely related collagen-specific receptor tyrosine kinases (RTK) that recognize and bind several types of collagen (5-7).”
BackgroundFuruyama, K., Kawaguchi, Y., Akiyama, H., Horiguchi, M., Kodama, S., Kuhara, T., Hosokawa, S., Elbahrawy, A., Soeda, T., Koizumi, M., et al. (2010) · Nature Genetics · doi:10.1038/ng.722 · Cited by 841 · cited 3×
“Sox9 is expressed in the malignant epithelium and is confined to the duct-like cells; differentiated acinar and endocrine cells do not express Sox9 (36, 37).”
Background
Cited by
Sorted by citations
Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321
Yuan, Z., Li, Y., Zhang, S., Wang, X., Dou, H., Yu, X., Zhang, Z., Yang, S., & Xiao, M. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01744-8 · Cited by 977
“These results depict a distinguish role of collagen in PDAC compared to other cancers.”
BackgroundInfluentialExtracellular matrix and its therapeutic potential for cancer treatment
Huang, J., Zhang, L., Wan, D., Zhou, L., Zheng, S., Lin, S., & Qiao, Y. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00544-0 · Cited by 962
“Aguilera et al.(500) knocked down DDR1 by siRNA and found that migration was inhibited in pancreatic ductal adenocarcinoma cells.”
BackgroundPancreatic cancer stroma: an update on therapeutic targeting strategies
Hosein, A. N., Brekken, R. A., & Maitra, A. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0300-1 · Cited by 950
Self-citationThe role of collagen in cancer: from bench to bedside
Xu, S., Xu, H., Wang, W., Li, S., Li, H., Li, T., Zhang, W., Yu, X., & Liu, L. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-2058-1 · Cited by 735
Microenvironmental Determinants of Pancreatic Cancer
Heßmann, E., Buchholz, S., Demir, İ. E., Singh, S. K., Gress, T. M., Ellenrieder, V., & Neeße, A. (2020) · Physiological Reviews · doi:10.1152/physrev.00042.2019 · Cited by 336
The Extracellular Matrix and Pancreatic Cancer: A Complex Relationship
Weniger, M., Honselmann, K. C., & Liss, A. S. (2018) · Cancers · doi:10.3390/cancers10090316 · Cited by 280
“DDR1 was effectively inhibited by the orally available small molecule kinase inhibitor 7rh, resulting in decreased tumor burden and improved response to concomitant chemotherapy in xenograft and genetically engineered mouse models of PDAC [68].”
BackgroundExtracellular matrix stiffness: Mechanisms in tumor progression and therapeutic potential in cancer
Zhang, M., & Zhang, B. (2025) · Experimental Hematology & Oncology · doi:10.1186/s40164-025-00647-2 · Cited by 269
“Aguilera et al. demonstrated that pharmacological inhibition of DDR1 using an ATP-competitive, orally bioavailable small-molecule kinase inhibitor reduced colony formation and migration of pancreatic tumor cells [192].”
Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome
Su, H., Yang, F., Fu, R., Trinh, B., Sun, N., Liu, J., Kumar, A., Baglieri, J., Siruno, J., Le, M., et al. (2022) · Nature · doi:10.1038/s41586-022-05169-z · Cited by 221
“Although inhibition of DDR1 reduces the growth of mouse PDAC 24 , the ability of DDR1 to control tumour metabolism by stimulating macropinocytosis and mitochondrial biogenesis was unknown.”
Bulle, A. S., & Lim, K. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00341-1 · Cited by 208
“Inhibition of DDR1 reduces collagen-induced PDAC tumorigenicity via suppression of protein tyrosine kinase 2 (Pyk2) and pseudopodium-enriched atypical kinase 1 (PEAK1) activation, thereby enhancing the effect of chemotherapy in preclinical models.(110)”
BackgroundDDR1-induced neutrophil extracellular traps drive pancreatic cancer metastasis
Deng, J., Kang, Y., Cheng, C.-C., Li, X., Dai, B., Katz, M. H. G., Men, T., Kim, M. P., Koay, E. J., Huang, H., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.146133 · Cited by 160
“Targeting DDR1 reduces neutrophil-mediated cancer cell invasion Our previous study demonstrated that the specific DDR1 inhibitor 7rh benzamide can improve the efficacy of standard-of-care chemotherapy in PDAC (12).”
BackgroundInfluentialSelf-citationFibroblasts in Pancreatic Ductal Adenocarcinoma: Biological Mechanisms and Therapeutic Targets
Whittle, M. C., & Hingorani, S. R. (2019) · Gastroenterology · doi:10.1053/j.gastro.2018.12.044 · Cited by 134
Zhang, J., Hu, Z., Horta, C. A., & Yang, J. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.12.002 · Cited by 106
“Inhibition of DDR1 by 7rh also hindered tumor development in pancreatic ductal adenocarcinoma[251,253].”
BackgroundStroma-Targeting Therapy in Pancreatic Cancer: One Coin With Two Sides?
Jiang, B., Zhou, L., Lü, J., Wang, Y., Liu, C., You, L., & Guo, J. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.576399 · Cited by 104
“In fact, the selective small molecule inhibitor of DDR1 reduced collagen deposition and improved the response to chemotherapy in PDAC mouse models (32).”
BackgroundSong, K., Yu, Z., Zu, X., Li, G., Hu, Z., & Xue, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810509 · Cited by 97
Dai, W., Liu, S., Wang, S., Zhao, L., Yang, X., Zhou, J., Wang, Y., Zhang, J., Zhang, P., Ding, K., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00563-x · Cited by 82
“, nasopharyngeal carcinoma, pancreatic cancer).(46,47) The differential sensitivity may due to discrepancy in cell type context and culture system.”
BackgroundSelf-citationTan, X., Li, C., Yang, R., Zhao, S., Li, F., Li, X., Chen, L., Wan, X., Liu, X., Yang, T., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01205 · Cited by 68
Cell-Matrix Interactions and Matricrine Signaling in the Pathogenesis of Vascular Calcification
Ngai, D., Lino, M., & Bendeck, M. P. (2018) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2018.00174 · Cited by 70
“DDRs have been implicated in cellular processes regulating migration, adhesion, proliferation, as well as in the pathogenesis of fibrosis (86, 87), cancer (88, 89), atherosclerosis (90–92), and vascular calcification (16, 65).”
BackgroundMultitasking discoidin domain receptors are involved in several and specific hallmarks of cancer
Henriet, E., Sala, M., Hammoud, A. A., Tuariihionoa, A., Martino, J. S. D., Ros, M., & Saltel, F. (2018) · Cell Adhesion & Migration · doi:10.1080/19336918.2018.1465156 · Cited by 65
Zhu, D., Huang, H., Pinkas, D. M., Luo, J., Ganguly, D., Fox, A. E., Arner, E. N., Xiang, Q., Tu, Z.-C., Bullock, A. N., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00365 · Cited by 64
Self-citationXiong, Y., Zhang, X., Zhu, J., Zhang, Y., Pan, Y., Wu, Y. Z., Zhao, J., Liu, J., Lu, Y., Liang, H., et al. (2023) · Cell Death and Differentiation · doi:10.1038/s41418-023-01166-5 · Cited by 67
DDR1 promotes hepatocellular carcinoma metastasis through recruiting PSD4 to ARF6
Zhang, X., Hu, Y., Pan, Y., Xiong, Y., Zhang, Y., Han, M., Dong, K., Song, J., Liang, H., Ding, Z., et al. (2022) · Oncogene · doi:10.1038/s41388-022-02212-1 · Cited by 61
“For example, Nilotinib inhibited DDR1 kinase activity and reduced the invasion and metastasis of colorectal cancer cells [14].”
BackgroundLai, S. L., Tan, M. L. M., Hollows, R. J., Robinson, M., Ibrahim, M., Margielewska, S., Parkinson, E. K., Ramanathan, A., Zain, R. B., Mehanna, H. M., et al. (2019) · Cancers · doi:10.3390/cancers11111766 · Cited by 60
“This is consistent with previous reports that showed that the inhibition of DDR1 can improve the efficacy of chemotherapy in pancreatic ductal carcinoma [21] and that the ectopic expression of DDR1 significantly increased the survival of lymphoma cells after chemotherapeutic drug treatment [22].”
BackgroundResultJin, H., Ham, I., Oh, H. J., Bae, C. A., Lee, D., Kim, Y.-B., Son, S., Chwae, Y., Han, S., Brekken, R. A., et al. (2018) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-17-0710 · Cited by 52
“Blocking DDR1 signaling through 7rh represses the effects of CAFs on gastric carcinomas We next evaluated the effect of 7rh, a specific inhibitor of DDR1 (20), which may be a new candidate therapeutic agent.”
BackgroundSelf-citationShen, T., & Guo, Q. (2018) · Medical Science Monitor · doi:10.12659/msm.913479 · Cited by 51
DDR1 promotes breast tumor growth by suppressing antitumor immunity
Zhong, X., Zhang, W., & Sun, T. (2019) · Oncology Reports · doi:10.3892/or.2019.7338 · Cited by 49
Recent advances in understanding cancer-associated fibroblasts in pancreatic cancer
Huang, H., & Brekken, R. A. (2020) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00079.2020 · Cited by 49
Self-citationInhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma
Nokin, M., Darbo, É., Travert, C., Drogat, B., Lacouture, A., José, S. S., Cabrera-Benítez, N. E., Turcq, B., Prouzet‐Mauleon, V., Falcone, M., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.137869 · Cited by 47
“Recently, DDR1 inhibition in a mouse model of pancreatic ductal adenocarcinoma increased tumor response to standard-of-care chemotherapy regimens (45).”
BackgroundSelf-citationYang, Y., Sun, H., Yu, H., Wang, L., Gao, C., Mei, H., Jiang, X., & Ji, M. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06070-9 · Cited by 48
“In pancreatic ductal adenocarcinoma (PDAC), collagen exerts a promotional effect on PDAC growth through cCOLI-DDR1-NF-κB-p62-NRF2 signaling [17, 18].”
Signaling by discoidin domain receptor 1 in cancer metastasis
Gadiya, M. M., & Chakraborty, G. (2018) · Cell Adhesion & Migration · doi:10.1080/19336918.2018.1520556 · Cited by 46
“nation with conventional chemotherapy significantly reduces pancreatic tumor growth in preclinical pancreatic cancer PDX model [88].”
BackgroundThe Next Wave of Stroma-Targeting Therapy in Pancreatic Cancer
Huang, H., & Brekken, R. A. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-3751 · Cited by 44
“Small-molecule–mediated selective inhibition of DDR1 reduces collagen deposition, decreases epithelial plasticity, and improves the response to chemotherapy in GEMMs of PDA (9).”
BackgroundSelf-citationTao, Y., Wang, R., Lai, Q., Wu, M., Wang, Y., Jiang, X., Zeng, L., Zhou, S., Li, Z., Yang, T., et al. (2019) · Molecular Oncology · doi:10.1002/1878-0261.12520 · Cited by 44
“, 2006) and pancreatic adenocarcinoma carcinoma cells (Aguilera et al., 2017) shows impaired growth of tumor xenograft in mice.”
BackgroundRuggeri, J. M., Franco-Barraza, J., Sohail, A., Zhang, Y., Long, D., Pasca di Magliano, M., Cukierman, E., Fridman, R., & Crawford, H. C. (2020) · The American Journal of Pathology · doi:10.1016/j.ajpath.2020.03.020 · Cited by 40
“Although paralysis limited our cohort size, the findings that Ddr1 / ; KPC mice generally do not present with metastatic disease are consistent with pharmacologic inhibition of DDR1 inhibiting PDA progression in a similar model.(23) On the basis of the consistent phenotype of a smaller pancreas found in the Ddr1 / ; K…”
MethodResultInfluentialLiang, D., Liu, L., Zhao, Y., Luo, Z., He, Y., Li, Y., Tang, S., Tang, J., & Chen, N. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1186712 · Cited by 48
“Combinations of DDR1 inhibitors and classical chemotherapeutics reduce tumor burden in orthotopic xenograft and orthotopic pancreatic cancer models (Aguilera et al., 2017).”
BackgroundGetting a grip on adhesion: Cadherin switching and collagen signaling
Huang, H., Wright, S., Zhang, J., & Brekken, R. A. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2019.04.002 · Cited by 42
Self-citationInflammation and Myeloid Cells in Cancer Progression and Metastasis
Deng, J., & Fleming, J. B. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.759691 · Cited by 44
Self-citationRas-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice
Tolani, B., Celli, A., Yao, Y., Tan, Y. Z., Fetter, R. D., Liem, C. R., de Smith, A. J., Vasanthakumar, T., Bisignano, P., Cotton, A. D., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01386-z · Cited by 44
“…n = 3. e , f , BLI of the entire mammalian V-ATPase complex ( e ; association protein concentrations: 30, 60, 120, 240 nM) and the individual human H subunit (ATP6V 1 H) ( f ; association protein concentrations, 16,800 and 21,000 nM) against biotinylated 249C loaded onto streptavidin sensor tips.”
Photodynamic Therapy for Pancreatic Ductal Adenocarcinoma
Karimnia, V., Slack, F. J., & Celli, J. P. (2021) · Cancers · doi:10.3390/cancers13174354 · Cited by 42
“to improve the outcome of PDAC treatment [57].”
BackgroundComplex roles of discoidin domain receptor tyrosine kinases in cancer
Mehta, V., Chander, H., & Munshi, A. (2021) · Clinical & Translational Oncology · doi:10.1007/s12094-021-02552-6 · Cited by 37
Baltes, F., Caspers, J., Henze, S., Schlesinger, M., & Bendas, G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21144956 · Cited by 33
“have demonstrated that 7rh reduced DDR1 signaling up to 500 nM in a time-dependent manner in vitro in pancreatic cells and increased response to gemcitabine in vivo in a xenograft model [61].”
Majo, S., & Auguste, P. (2021) · Cancers · doi:10.3390/cancers13071725 · Cited by 38
Innate and adaptive immune-directed tumour microenvironment in pancreatic ductal adenocarcinoma
Joseph, A. M., Aiyan, A. A., al-Ramadi, B. K., Singh, S. K., & Kishore, U. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1323198 · Cited by 36
“A small molecule inhibitor targeting DDR1 resulted in a decrease in fi brillar collagen deposition and an enhancement in the ef fi cacy of chemotherapy in orthotopic mouse models of PDAC (39).”
BackgroundNovel Targets for Therapy of Renal Fibrosis
Prakoura, N., Hadchouel, J., & Chatziantoniou, C. (2019) · Journal of Histochemistry & Cytochemistry · doi:10.1369/0022155419849386 · Cited by 32
Diehl, J. N., Klomp, J. E., Snare, K. R., Hibshman, P. S., Blake, D. R., Kaiser, Z. D., Gilbert, T. S. K., Baldelli, E., Pierobon, M., Papke, B., et al. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101335 · Cited by 30
“DDR1 is an RTK that transduces collagen-mediated proliferative signaling from stroma-associated extracellular matrix (46), and pharmacological inhibition of DDR1 function impaired PDAC growth in vivo in a mouse model (47, 48).”
Mancarella, C., & Scotlandi, K. (2017) · Journal of Molecular Endocrinology · doi:10.1530/jme-17-0250 · Cited by 28
Wasinski, B. D., Sohail, A., Bonfil, R. D., Kim, S., Saliganan, A. D., Polin, L., Bouhamdan, M., Kim, H.-R. C., Prunotto, M., & Fridman, R. A. (2020) · Scientific Reports · doi:10.1038/s41598-020-59028-w · Cited by 28
The Impact of Integrin-Mediated Matrix Adhesion on Cisplatin Resistance of W1 Ovarian Cancer Cells
von Rekowski, K. W., König, P., Henze, S., Schlesinger, M., Zawierucha, P., Januchowski, R., & Bendas, G. (2019) · Biomolecules · doi:10.3390/biom9120788 · Cited by 27
“Discoidin domain receptor 1 (DDR1) appears a potential candidate for collagen binding, which has recently been associated with malignancy, metastasis, and resistance in other tumor entities, such as breast cancer [32], gastric cancer [33], or pancreatic ductal adenocarcinomas [34].”
BackgroundZhu, J., Zhang, K., Chen, Y., Ge, X., Wu, J., Xu, P., & Yao, J. J. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05307-3 · Cited by 30
“0 [26], Bisque [27], Coex [28].”
Collagen remodeling-mediated signaling pathways and their impact on tumor therapy
Yuan, Z., Lin, B., Wang, C., Yan, Z., Yang, F., & Su, H. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.108330 · Cited by 26
“Additionally, 7rh demonstrated potent antiproliferative effects against liposarcomas and PDAC expressing high levels of DDR1 (205, 206).”
Yan, B., Liu, L., Zhao, L., Hinz, U., Luo, Y., An, X., Gladkich, J., Torre, C. D. L., Huang, Z., Schrapel, D., et al. (2022) · Matrix Biology · doi:10.1016/j.matbio.2022.11.002 · Cited by 26
Lorusso, G., Rüegg, C., & Kuonen, F. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01231 · Cited by 28
“7rh (DDR1 inhibitor) – Gastric, pancreas Tumor growth (88, 89)”
Kuznetsova, A. V., Попова, О. П., Panchenkov, D. N., Dyuzheva, Т. G., & Aa, I. (2022) · Clinical and Experimental Medicine · doi:10.1007/s10238-022-00886-1 · Cited by 24
“In PDAC, activation of DDR1 on tumor cells stimulates pro-oncogenic signaling via protein tyrosine kinase 2 (PYK2) [62].”
BackgroundCui, G., Deng, S., Zhang, B., Wang, M., Lin, Z., Lan, X., Li, Z., Yao, G., Yu, M., & Yan, J. (2024) · Advanced Science · doi:10.1002/advs.202402107 · Cited by 25
Creeden, J. F., Alganem, K., Imami, A. S., Henkel, N., Brunicardi, F. C., Liu, S., Shukla, R., Tomar, T., Naji, F., & McCullumsmith, R. E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228823 · Cited by 22
“DDR1 inhibition reduces collagen-mediated tumorigenicity in PDAC [118]”
BackgroundPrecision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment
Vitorakis, N., Gargalionis, A. N., Papavassiliou, K. A., Adamopoulos, C., & Papavassiliou, A. G. (2024) · Cancers · doi:10.3390/cancers16162876 · Cited by 25
“…and ECM remodeling, using various inhibitors and drugs, to enhance drug delivery, reduce fibrosis, and improve therapeutic outcomes [82,152–158] Targeting TME immune cells CSF1R inhibitors (Cabiralizumab), PD1 checkpoint inhibitor (nivolumab), Myc blockers CD40 agonists, galectin-9…”
BackgroundSığırlı, S., & Karakaş, D. (2025) · Cancer Medicine · doi:10.1002/cam4.70788 · Cited by 24
“Moreover, this inhibition was shown to reduce tumor burden and enhance response to chemotherapy in orthotopic xenograft models [132].”
Stroma-targeting strategies in pancreatic cancer: a double-edged sword
Liu, X., Iovanna, J., & Santofimia‐Castaño, P. (2022) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-022-00941-1 · Cited by 21
“treated PDAC mice with the DDR1 inhibitor 7rh combined with gemcitabine and paclitaxel, which prolonged median survival and significantly reduced DDR1 activation and downstream signaling, as well as primary tumor burden [1].”
MethodXu, H., Tan, M., Hou, G., Sang, Y.-Z., Lin, L., Gan, X.-C., Cao, X., & Liu, A. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06344-4 · Cited by 20
“These analyses provided insights into the cellular response mechanisms induced by SH2 TrM-(Arg)9 through the DDR1/ PYK2/ERK-mediated signaling.”
BackgroundVillalba-Esparza, M., Redín, E., Expósito, F., Pajares, M. J., Sainz, C., Hervás, D., Guruceaga, E., Díaz‐Lagares, Á., Cirauqui, C., Redrado, M., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-51066-3 · Cited by 19
Li, Q., Yang, C., Li, J., Wang, R., Min, J., Song, Y., & Su, H. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06778-8 · Cited by 21
“The DDR1 inhibitor 7rh enhances chemotherapy efficacy in KPC mice and reduces PC cell migration [155].”
Inhibitors of Discoidin Domain Receptor (DDR) Kinases for Cancer and Inflammation
Denny, W. A., & Flanagan, J. U. (2021) · Biomolecules · doi:10.3390/biom11111671 · Cited by 18
“[42] showed collagen-induced activation of DDR1 by pro-tumorigenic signaling through the kinases PYK2 and PEAK1, and that inhibition of DDR1 with 32 showed high efficacy, in combination with chemotherapy, in orthotopic xenografts of pancreatic adenocarcinomas.”
BackgroundLi, J., Zhang, W., Chen, L., Wang, X., Liu, J., Huang, Y., Qi, H., Chen, L., Wang, T., & Li, Q. (2024) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2024.189225 · Cited by 18
Chemoresistance in pancreatic ductal adenocarcinoma: Overcoming resistance to therapy
Bhoopathi, P., Mannangatti, P., Das, S. K., Fisher, P. B., & Emdad, L. (2023) · Advances in cancer research · doi:10.1016/bs.acr.2023.02.010 · Cited by 19
Zhou, H., Wang, W., Cai, Z., Jia, Z.-Y., Li, Y., He, W., Li, C., & Zhang, B. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02646-7 · Cited by 17
“Some small molecules targeting these kinases such as fasudil, defactinib, and 7rh exhibited the capacity of inhibiting stroma formation and show some promise for PDAC therapy [12, 23].”
BackgroundA network map of discoidin domain receptor 1(DDR1)-mediated signaling in pathological conditions
Dagamajalu, S., Balaya, R. D. A., Suchitha, G. P., Rai, A. B., Kumar, S., Joshi, S., Raju, R., & Prasad, T. S. K. (2022) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-022-00714-x · Cited by 16
Luo, L., Wang, X., Liao, Y.-P., Xu, X., Chang, C. H., & Nel, A. E. (2024) · Nano Today · doi:10.1016/j.nantod.2023.102058 · Cited by 16
Bonfil, R. D., Chen, W., Vranić, S., Sohail, A., Shi, D., Jang, H., Kim, H.-R., Prunotto, M., & Fridman, R. A. (2021) · Cancer Cell International · doi:10.1186/s12935-021-02206-1 · Cited by 15
Elucidating the link between collagen and pancreatic cancer: what’s next?
Hamada, S., & Masamune, A. (2018) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2018.1448268 · Cited by 15
Rattanasinchai, C., Navasumrit, P., & Ruchirawat, M. (2022) · Scientific Reports · doi:10.1038/s41598-022-26747-1 · Cited by 15
Liu, L., Zhao, L., Yang, L., Chai, M., Liu, Z., Ma, N., Wang, Y., Wu, Q., Guo, J., Zhou, F., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00162 · Cited by 15
Self-citationTumor DDR1 deficiency reduces liver metastasis by colon carcinoma and impairs stromal reaction
Romayor, I., Márquez, J., Benedicto, A., Herrero, A., Arteta, B., & Olaso, E. (2021) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00078.2021 · Cited by 12
Li, Y., Tang, Y., Chen, S., Liu, Y., Wang, S., Tian, Y., Wang, C., Teng, Z., & Lu, G. (2019) · RSC Advances · doi:10.1039/c9ra02180a · Cited by 11
A putative role for Discoidin Domain Receptor 1 in cancer chemoresistance
Ambrogio, C., Darbo, É., Lee, S. W., & Santamarı́a, D. (2018) · Cell Adhesion & Migration · doi:10.1080/19336918.2018.1445954 · Cited by 13
“Likewise, pharmacological inhibition of DDR1 resulted in increased therapeutic response in PDAC when administered concomitantly with cytotoxic chemotherapy [12].”
BackgroundDeep proteome profiling of human mammary epithelia at lineage and age resolution
Hinz, S., Manousopoulou, A., Miyano, M., Sayaman, R. W., Aguilera, K. Y., Todhunter, M. E., Lopez, J. C., Sohn, L. L., Wang, L. D., & LaBarge, M. A. (2021) · iScience · doi:10.1016/j.isci.2021.103026 · Cited by 11
“By utilizing the DDR1-specific drug 7rh, which was previously utilized to target DDR1 signaling in pancreatic cancer (Aguilera et al., 2017), phosphorylation of both DDR1 and PEAK1 were reduced in HMECs from older women (Figure 5D).”
BackgroundMethodInfluentialSelf-citationParallels between the extracellular matrix roles in developmental biology and cancer biology
Yuzhalin, A. E. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2021.09.010 · Cited by 11
Liu, S., Li, X., Chen, C., Lin, X., Zuo, W., Peng, C. Y., Jiang, Q., Huang, W., & He, G. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.116100 · Cited by 11
Discoidin domain receptor 1 as a potent therapeutic target in solid tumors
Bibi, S., Zeng, W., Zheng, P., Mehmandousti, S. M. M., & Jin, T. (2024) · hLife · doi:10.1016/j.hlife.2024.01.003 · Cited by 9
ECM, integrins, and DDRs: A nexus of cancer progression, therapy, and future directions
Azim, M. A., & Martino, J. S. D. (2025) · Matrix Biology · doi:10.1016/j.matbio.2025.04.002 · Cited by 9
Wang, X., Ju, Z., Liu, S., Qi, F., Xin, C., Li, X., Gao, Y. P., Dan, F., Qu, Y., Ren, Z., et al. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117750 · Cited by 9
Pancreatic cancer: genetics, disease progression, therapeutic resistance and treatment strategies
Singh, K., Shishodia, G., & Koul, H. K. (2021) · Journal of Cancer Metastasis and Treatment · doi:10.20517/2394-4722.2021.96 · Cited by 9
“Mouse PDAC [70] Hyaluronic acid (HA) Lowered interstitial fluid pressure in the tumors and inhibited tumor growth due to improved drug delivery KPC mice [71,72] PEGylated hyaluronidase a (PEGPH20, an enzyme that temporarily degrades HA) plus gemcitabine In vitro, orthotopic and KPC mice [79,82]”
Hu, W., Huang, Q., Chen, L., Geng, S., Zhang, H., Chen, H., Liu, X., Zhong, J., Su, F., Shao, C., et al. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07062-5 · Cited by 8
“This inhibitor has demonstrated significant therapeutic potential in various human cancer models, including pancreatic cancer, non-small cell lung cancer, and gastric cancer [59–61].”
Huang, H., & Brekken, R. A. (2020) · American Journal Of Pathology · doi:10.1016/j.ajpath.2020.05.005 · Cited by 8
“Consistent with this, pharmacologic inhibition of DDR1 significantly reduces PDA tumor growth, reduces cancer cell invasiveness, and improves chemotherapy response in vivo.(16,17) DDR1 activity has also been implicated in driving tumor progression in other cancer types.”
BackgroundSelf-citationMaghathe, T., Miller, W. K., Mugge, L. A., Mansour, T. R., & Schroeder, J. L. (2020) · Journal of Neurosurgical Sciences · doi:10.23736/s0390-5616.18.04419-3 · Cited by 8
Emerging strategies and translational advancements of DDR1 in oncology
Luo, Y., Liu, T., Pei, J., Xu, S., Liu, J., & Yu, J. (2025) · Discover Oncology · doi:10.1007/s12672-025-02107-z · Cited by 7
Antibody-drug conjugates targeting DDR1 as a novel strategy for treatment of breast cancer
Tao, Y., Lu, Y., Xue, T., Lai, Q., Song, H., Chen, X., Guo, C., Yang, J., & Wang, Y. (2024) · Journal of drug targeting · doi:10.1080/1061186x.2024.2386621 · Cited by 7
“it has been reported that DDR1 is upregulated in a variety of human cancers, especially epithelial cancers [10–12]. here, to assess DDR1 expression in cancer, we conducted ihc analyses of DDR1 in six different malignant tumours that developed from epithelial cells, including breast cancer,…”
Liu, A., Zhang, S., Wang, M., Zhang, L., Xu, S., Nasimian, A., Li, S., Zhao, S., Cao, X., Tian, J., et al. (2023) · Molecular Carcinogenesis · doi:10.1002/mc.23637 · Cited by 7
The hallmarks of pancreatic cancer
Kane, L. E., Hackett, D., Lyons, R. G., Ryan, B. M., & Maher, S. G. (2026) · Cancer Letters · doi:10.1016/j.canlet.2026.218437 · Cited by 8
Genetic and pharmacological tools to study the role of discoidin domain receptors in kidney disease
Borza, C. M., Bolás, G., & Pozzi, A. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1001122 · Cited by 6
“, 2021), or blocking their kinase activity (Kothiwale et al., 2015; Ambrogio et al., 2016; Aguilera et al., 2017; Hur et al., 2017; Jin et al., 2018).”
BackgroundWu, L., Zhao, X., Ma, H., Zhang, L., & Li, X. (2022) · International Journal of General Medicine · doi:10.2147/ijgm.s348110 · Cited by 4
Inhibition of discoidin domain receptor 1 as a new therapeutic strategy for osteosarcoma
Jing-lu, W., Walker, R. L., Hornicek, F. J., Shi, H., & Duan, Z. (2024) · The FASEB Journal · doi:10.1096/fj.202401508rr · Cited by 4
“As shown in Figure 7C, the addition of 0.5 μ M of 7rh for 24, 48, and 72 h led to a time-dependent decrease in cell migration in both cell lines compared to the untreated cells ( p .05).”
InfluentialZhu, X., Yao, M., Zhang, B., Zhu, C., Zhu, F., Shen, T., & Fang, C. (2020) · Oral Surgery Oral Medicine Oral Pathology and Oral Radiology · doi:10.1016/j.oooo.2020.10.010 · Cited by 4
Research progress of PYK2 in digestive system diseases
Duan, Y., Xie, M., Wang, H., Chen, S., Hu, J. S., Chen, X., Jia, H. P., Zhang, N., Peng, L., Li, X., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1614589 · Cited by 3
Self-citationKhan, T. B., Choudhary, N., Sharma, S., Kumar, D., Kaushik, U., Gupta, V., Gowri, S., Faiyazuddin, M., & Webster, T. J. (2026) · Advances in Cancer Biology - Metastasis · doi:10.1016/j.adcanc.2026.100188 · Cited by 4
Wang, Q., Hao, F., Ning, L., & Sun, C. (2024) · PubMed · doi:10.14670/hh-18-705 · Cited by 3
Hai, M., Liu, Y., Xiong, L., Li, G., Wang, G., Zhang, H., Shuai, J., Chen, G., & Liu, L. (2020) · Chinese Physics B · doi:10.1088/1674-1056/ab9c02 · Cited by 2
Dean, D. C., Feng, W., Walker, R. L., Thanindratarn, P., Temple, H. T., Trent, J. C., Rosenberg, A. E., Hornicek, F. J., & Duan, Z. (2023) · Clinical Orthopaedics and Related Research · doi:10.1097/corr.0000000000002865 · Cited by 2
“Inhibition of DDR1 with 7RH has also shown ef fi cacy in combination with other chemotherapeutics or immuno-toxin therapy in several cancer cell lines and tumor-orthotopic xenografts, where it reduced DDR1 activation and downstream signaling, primary tumor burden, and chemoresistance [1, 2, 18].”
BackgroundInfluentialDiscoidin domain receptor 1 as a promising biomarker for high-grade gliomas
Erdem, D., Günaldı, M., Karaman, İ., Adilay, U., Yılmaz, İ., Eseoğlu, M., Avcıkurt, A. S., Işıksaçan, N., Erdoğan, U., & Günaldı, Ö. (2022) · Journal of Cancer Research and Therapeutics · doi:10.4103/jcrt.jcrt_708_21 · Cited by 2
Huang, H., Kovacs, M. E., Aguilera, K. Y., & Brekken, R. A. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816435-8.00007-9 · Cited by 2
Self-citationDing, Y., Zhao, P., Yan, J., Li, Y., Wang, Z., Lu, Y., Zhang, Y., Chen, H., Zhang, W., Luan, X., et al. (2026) · Cancer and Metastasis Reviews · doi:10.1007/s10555-026-10366-7 · Cited by 1
“Collagen receptors DDR1 and DDR2 sense matrix density and alignment and provide a slower but sustained receptor tyrosine kinase input that amplifies adhesion-derived tension through crosstalk with integrin signaling [104].”
Self-citationDDR1 in pancreatic adenocarcinoma: unraveling the mechanisms of immune exclusion
Cheng, L., Wei, L., Chen, Q., Li, P., & Zhang, D. (2024) · Scandinavian Journal of Gastroenterology · doi:10.1080/00365521.2024.2443505 · Cited by 1
“…orally available small molecule kinase inhibitor of DDR1) in combination with chemotherapy showed significant efficacy in in situ xenografts and autologous pancreatic tumors, in which it significantly reduced DDR1 activation and downstream signaling, and lowered primary tumor burden [27].”
Metadata
- Authors
- Aguilera, K. Y., Huang, H., Du, W., Hagopian, M. M., Wang, Z., Hinz, S., Hwang, T. H., Wang, H., Fleming, J. B., Castrillon, D. H., Ren, X., Ding, K., & Brekken, R. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Jinan University (CN)
- The University of Texas MD Anderson Cancer Center (US)
- 6Department of Clinical Science, UT Southwestern Medical Center, Dallas, Texas.
- Corresponding author
- Brekken, Rolf A.
- ORCID
- Venue
- Molecular Cancer Therapeutics
- Published
- 2017-11-01
- Volume
- 16
- Issue
- 11
- Pages
- 2473-2485
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC5669827
- OpenAlex
- W2751614779
- Cited by
- 118
- References
- 61
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 17 · 2023: 12 · 2022: 15 · 2021: 16 · 2020: 15 · 2019: 15 · 2018: 9 · 2017: 1
- FWCI
- 4.82
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01CA118240, U54 CA210181, F31 CA168350)
- CPRIT (RP160211)
- National Science Fund (#81425021)
- Guangdong province (#2016A050502041)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- DDR1, pancreatic ductal adenocarcinoma, collagen signaling, extracellular matrix, Pyk2, PEAK1, kinase inhibitors, chemosensitization, tumor cell migration, tumor cell proliferation, combination chemotherapy
- MeSH terms
- Discoidin Domain Receptor 1, Adenocarcinoma, Animals, Cell Adhesion, Cell Movement, Collagen, Humans, Protein-Tyrosine Kinases, Signal Transduction, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, Focal Adhesion Kinase 1, Small Molecule Libraries, Carcinogenesis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
