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DDR1 inhibition as a new therapeutic strategy for colorectal cancer.

ABSTRACT: The clinical management of metastatic colorectal cancer (mCRC) is still a major challenge. Recently, we discovered that nilotinib, an approved treatment for chronic myeloid leukaemia, inhibits invasive and metastatic properties of CRC cells by targeting the kinase activity of receptor for collagens DDR1 (Discoïdin Domain Receptor tyrosine kinase 1), suggesting that nilotinib could be an effective strategy to treat mCRC.

SUBMITTER: Sirvent A

PROVIDER: S-EPMC6149912 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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DDR1 inhibition as a new therapeutic strategy for colorectal cancer.

Sirvent Audrey A Lafitte Marie M Roche Serge S

Molecular & cellular oncology 20180723 4

The clinical management of metastatic colorectal cancer (mCRC) is still a major challenge. Recently, we discovered that nilotinib, an approved treatment for chronic myeloid leukaemia, inhibits invasive and metastatic properties of CRC cells by targeting the kinase activity of receptor for collagens DDR1 (Discoïdin Domain Receptor tyrosine kinase 1), suggesting that nilotinib could be an effective strategy to treat mCRC. ...[more]

PMID: 30250919

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Inhibition of DDR1-BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer.

Project description:The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. Here, we show that nilotinib, a clinically approved drug for chronic myeloid leukaemia, strongly inhibits human CRC cell invasion in vitro and reduces their metastatic potential in intrasplenic tumour mouse models. Nilotinib acts by inhibiting the kinase activity of DDR1, a receptor tyrosine kinase for collagens, which we identified as a RAS-independent inducer of CRC metastasis. Using quantitative phosphoproteomics, we identified BCR as a new DDR1 substrate and demonstrated that nilotinib prevents DDR1-mediated BCR phosphorylation on Tyr177, which is important for maintaining β-catenin transcriptional activity necessary for tumour cell invasion. DDR1 kinase inhibition also reduced the invasion of patient-derived metastatic and circulating CRC cell lines. Collectively, our results indicate that the targeting DDR1 kinase activity with nilotinib may be beneficial for patients with mCRC.

| S-EPMC5887546 | biostudies-literature

In vivo DDR1 signalling - Inhibition of DDR1-BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer

Project description:The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. For instance, patients harbouring oncogenic mutations in RAS signalling do not respond to anti-EGFR targeted treatment. Therefore, RAS-independent therapies are needed. Interestingly nilotinib, a clinically approved drug for chronic myeloid leukaemia, inhibits human CRC cell invasion in vitro and reduces their metastatic potential in intrasplenic tumour mouse models. Nilotinib acts by inhibiting the kinase activity of DDR1, a receptor tyrosine kinase for collagens, which we identified as a RAS-independent inducer of CRC metastasis. Using quantitative phosphoproteomics, we identified BCR as a new DDR1 substrate and demonstrated that nilotinib prevents DDR1-mediated BCR phosphorylation on Tyr177, which is important for maintaining -catenin transcriptional activity necessary for tumour cell invasion. DDR1 kinase inhibition also reduced the invasion of patient-derived metastatic and circulating CRC cell lines.

2018-01-31 | PXD008546 | Pride

In vitro DDR1 signalling - Inhibition of DDR1-BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer

2018-01-31 | PXD008582 | Pride

Therapeutic strategy in unresectable metastatic colorectal cancer.

Project description:While surgery is the cornerstone treatment for early-stage colorectal cancer, chemotherapy is the first treatment option for metastatic disease when tumor lesions are frequently not fully resectable at presentation. Mortality from colon cancer has decreased over the past 30 years, but there is still a huge heterogeneity in survival rates that can be mainly explained by patient and tumor characteristics, host response factors, and treatment modalities. The management of unresectable metastatic colorectal cancer is a global treatment strategy, which applies several lines of therapy, salvage surgery, maintenance, and treatment-free intervals. The individualization of cancer treatment is based on the evaluation of prognostic factors for survival (serum lactate dehydrogenase level, performance status), and predictive factors for treatment efficacy [Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status]. The available treatment modalities for metastatic colorectal cancer are chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic agents (e.g. bevacizumab), and anti-epidermal growth factor agents (cetuximab, panitumumab). The increasing number of active compounds dictates the strategy of trials evaluating these treatments either in combination or sequentially. Alternative outcomes that can be measured earlier than overall survival are needed to shorten the duration and reduce the size and cost of clinical trials.

| S-EPMC3296081 | biostudies-other

New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function.

Project description:Autophagy inhibition has been proposed to be a potential therapeutic strategy for cancer, however, few autophagy inhibitors have been developed. Recent studies have indicated that lysosome and autophagy related 4B cysteine peptidase (ATG4B) are two promising targets in autophagy for cancer therapy. Although some inhibitors of either lysosome or ATG4B were reported, there are limitations in the use of these single target compounds. Considering multi-functional drugs have advantages, such as high efficacy and low toxicity, we first screened and validated a batch of compounds designed and synthesized in our laboratory by combining the screening method of ATG4B inhibitors and the identification method of lysosome inhibitors. ATG4B activity was effectively inhibited in vitro. Moreover, 163N inhibited autophagic flux and caused the accumulation of autolysosomes. Further studies demonstrated that 163N could not affect the autophagosome-lysosome fusion but could cause lysosome dysfunction. In addition, 163N diminished tumor cell viability and impaired the development of colorectal cancer in vivo. The current study findings indicate that the dual effect inhibitor 163N offers an attractive new anti-cancer drug and compounds having a combination of lysosome inhibition and ATG4B inhibition are a promising therapeutic strategy for colorectal cancer therapy.

| S-EPMC7352571 | biostudies-literature

Therapeutic inhibition of SGK1 suppresses colorectal cancer.

Project description:Colorectal cancer (CRC) is one of the leading causes of death worldwide. Thus, the development of new therapeutic targets for CRC treatment is urgently needed. SGK1 is involved in various cellular activities, and its dysregulation can result in multiple cancers. However, little is known about its roles and associated molecular mechanisms in CRC. In present study, we found that SGK1 was highly expressed in tumor tissues compared with peri-tumor samples from CRC patients. In vitro experiments revealed that SGK1 overexpression promoted colonic tumor cell proliferation and migration and inhibited cell apoptosis induced by 5-fluorouracil (5-FU), while SGK1 shRNA and inhibitors showed the inverse effects. Using CRC xenograft mice models, we demonstrated that knockdown or therapeutic inhibition of SGK1 repressed tumor cell proliferation and tumor growth. Moreover, SGK1 inhibitors increased p27 expression and promoted p27 nuclear accumulation in colorectal cancer cells, and p27 siRNAs could attenuate the repression of CRC cell proliferation induced by SGK1 inhibitors. Collectively, SGK1 promotes colorectal cancer development via regulation of CRC cell proliferation, migration and survival. Inhibition of SGK1 represents a novel strategy for the treatment of CRC.

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Therapeutic strategy in unresectable metastatic colorectal cancer: an updated review.

Project description:Systemic therapy is the standard care for patients with unresectable advanced colorectal cancer (CRC), but salvage surgery of metastatic disease should be considered in the case of adequate tumor shrinkage. Several drugs and combinations are now available for use in treating patients with advanced CRC, but the optimal sequence of therapy remains unknown. Moreover, the administration of antitumor therapy can be modulated by periods of maintenance or treatment breaks rather than delivered as full therapy until disease progression or unacceptable toxicity, followed by reintroduction of prior full therapy when required, before switching to other drugs. Consequently, randomized strategy trials are needed to define the optimal treatment sequences. Molecular testing for Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) is mandatory but not sufficient to select appropriate patients for epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy.

| S-EPMC4406914 | biostudies-literature

Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer.

Project description:Aurora kinase B (AURKB) is a mitotic serine/threonine protein kinase that belongs to the aurora kinase family along with aurora kinase A (AURKA) and aurora kinase C (AURKC). AURKB is a member of the chromosomal passenger protein complex and plays a role in cell cycle progression. Deregulation of AURKB is observed in several tumors and its overexpression is frequently linked to tumor cell invasion, metastasis and drug resistance. AURKB has emerged as an attractive drug target leading to the development of small molecule inhibitors. This review summarizes recent findings pertaining to the role of AURKB in tumor development, therapy related drug resistance, and its inhibition as a potential therapeutic strategy for cancer. We discuss AURKB inhibitors that are in preclinical and clinical development and combination studies of AURKB inhibition with other therapeutic strategies.

| S-EPMC8037052 | biostudies-literature

Selective pharmacological inhibition of DDR1 prevents experimentally-induced glomerulonephritis in prevention and therapeutic regime.

Project description:BACKGROUND:Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase extensively implicated in diseases such as cancer, atherosclerosis and fibrosis. Multiple preclinical studies, performed using either a gene deletion or a gene silencing approaches, have shown this receptor being a major driver target of fibrosis and glomerulosclerosis. METHODS:The present study investigated the role and relevance of DDR1 in human crescentic glomerulonephritis (GN). Detailed DDR1 expression was first characterized in detail in human GN biopsies using a novel selective anti-DDR1 antibody using immunohistochemistry. Subsequently the protective role of DDR1 was investigated using a highly selective, novel, small molecule inhibitor in a nephrotoxic serum (NTS) GN model in a prophylactic regime and in the NEP25 GN mouse model using a therapeutic intervention regime. RESULTS:DDR1 expression was shown to be mainly limited to renal epithelium. In humans, DDR1 is highly induced in injured podocytes, in bridging cells expressing both parietal epithelial cell (PEC) and podocyte markers and in a subset of PECs forming the cellular crescents in human GN. Pharmacological inhibition of DDR1 in NTS improved both renal function and histological parameters. These results, obtained using a prophylactic regime, were confirmed in the NEP25 GN mouse model using a therapeutic intervention regime. Gene expression analysis of NTS showed that pharmacological blockade of DDR1 specifically reverted fibrotic and inflammatory gene networks and modulated expression of the glomerular cell gene signature, further validating DDR1 as a major mediator of cell fate in podocytes and PECs. CONCLUSIONS:Together, these results suggest that DDR1 inhibition might be an attractive and promising pharmacological intervention for the treatment of GN, predominantly by targeting the renal epithelium.

| S-EPMC5984769 | biostudies-literature

Organ preservation strategy: new therapeutic alternative in rectal cancer.

Project description:BackgroundThe therapeutic modalities for nonmetastatic rectal cancer are presently undergoing major changes. The standard treatment is multidisciplinary, combining radiotherapy, chemotherapy, and surgery. The aim of this minireview is to provide an update on the place of organ preservation in the treatment of nonmetastatic rectal cancer in 2022.Main textThe multimodal strategy based on initial radiochemotherapy followed by radical surgery with excision of the mesorectum has improved oncological results but at the expense of morbidity and sequelae altering life quality. The strategy of rectal preservation has been proposed since the 2000s after the publication of the results of the Brazilian study that proposed a simple surveillance after radiochemotherapy without surgery in good responders. In fact, preoperative radiochemotherapy was able to obtain a complete histological response in 10 to 30% of case. In view of this non-negligible percentage of tumor sterilization, which may well increase with the standardization of total neoadjuvant treatment, a strategy of organ preservation can be proposed in these patients to avoid morbidity and postoperative sequelae.Short conclusionThis nonoperative approach is currently widely studied in certain patients who have a complete response (clinical, endoscopic, and radiological). However, the selection of these patients is not simple and still complex.

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