Targeting Discoidin Domain Receptor 1 (DDR1) Signaling and Its Crosstalk with β1-Integrin Emerges as a Key Factor for Breast Cancer Chemosensitization upon Collagen Type 1 Binding

Abstract

Collagen type 1 (COL1) is a ubiquitously existing extracellular matrix protein whose high density in breast tissue favors metastasis and chemoresistance. COL1-binding of MDA-MB-231 and MCF-7 breast cancer cells is mainly dependent on β1-integrins (ITGB1). Here, we elucidate the signaling of chemoresistance in both cell lines and their ITGB1-knockdown mutants and elucidated MAPK pathway to be strongly upregulated upon COL1 binding. Notably, Discoidin Domain Receptor 1 (DDR1) was identified as another important COL1-sensor, which is permanently active but takes over the role of COL1-receptor maintaining MAPK activation in ITGB1-knockdown cells. Consequently, inhibition of DDR1 and ERK1/2 act synergistically, and sensitize the cells for cytostatic treatments using mitoxantrone, or doxorubicin, which was associated with an impaired ABCG2 drug efflux transporter activity. These data favor DDR1 as a promising target for cancer cell sensitization, most likely in combination with MAPK pathway inhibitors to circumvent COL1 induced transporter resistance axis. Since ITGB1-knockdown also induces upregulation of pEGFR in MDA-MB-231 cells, inhibitory approaches including EGFR inhibitors, such as gefitinib appear promising for pharmacological interference. These findings provide evidence for the highly dynamic adaptation of breast cancer cells in maintaining matrix binding to circumvent cytotoxicity and highlight DDR1 signaling as a target for sensitization approaches.

The Fibrosis-Targeted Collagen/Integrins Gene Profile Predicts Risk of Metastasis in Pulmonary Neuroendocrine Neoplasms

“…Recent studies have shown that several COL and ITG genes are increased in a variety of tumors, and have been associated with unfavorable outcomes. Among these, COL1A2, COL3A1, COL5A2, ITGA5, ITGAV, and ITGB1 have been especially noted (48)(49)(50)(51)(52)(53). Therefore, for all these reasons, we realize that COL1A2, COL3A1, COL5A2, ITGA5, ITGAV, and ITGB1 genes expression provide important predictive information about metastatic-free and overall survival in PNENs and our results now confirm the predictive importance of COL and ITG genes in PNENs.…”

The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer

“…DDR1 and DDR2 dysregulation has been linked to multiple forms of cancer. Many studies have shown that elevated DDR expression levels and/or mutations can be found in a number of cancer cell lines as well as primary tumor tissues including lung [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ], pancreas [ 48 ], prostate [ 49 ], breast [ 50 , 51 ], brain [ 52 , 53 ], ovary [ 54 , 55 ], liver [ 56 ], and others [ 57 , 58 , 59 , 60 , 61 , 62 , 63 ]. DDR1 was found to be a prognostic marker for non-small-cell lung carcinoma (NSCLC) patients.…”

The Yin and Yang of Discoidin Domain Receptors (DDRs): Implications in Tumor Growth and Metastasis Development

“…Today, the difficulty with patient management lies in the tumor heterogeneity that does not allow a universal treatment, as well as in the lack of effective treatment, which leads to the appearance of resistance and cancer relapse. Some researchers have highlighted the role of DDR1 in treatment resistance in lung [ 144 ], breast [ 151 ], pancreas [ 143 ], glioma [ 152 ], ovarian [ 153 ], and head and neck cancers [ 154 ]. For example, in glioblastoma, DDR1 drives chemoresistance by collaborating with the 14-3-3/BECN1 (Beclin 1)/AKT1 multiprotein complex to enhance cell survival, anti-autophagy, and resistance by AKT/mTOR signaling [ 152 ].…”