Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma

Nokin, Marie-Julie; Darbo, Élodie; Travert, Camille; Drogat, Benjamin; Lacouture, Aurélie; José, Sonia San; Cabrera, Nuria E.; Turcq, Béatrice; Prouzet‐Mauléon, Valérie; Falcone, Mattia; Villanueva, Alberto; Wang, Haiyun; Herfs, Michaël; Mosteiro, Miguel A.; Pujol, Jean-Louis; Maraver, Antonio; Barbacid, Mariano; Nadal, Ernest; Santamarı́a, David; Ambrogio, Chiara

doi:10.1172/jci.insight.137869

Cited by 17 publications

(16 citation statements)

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“…As a key component of the tumor extracellular matrix, type I collagen shows high density and distorted architecture in malignant cancer, linking it to tumor formation and metastasis [ 83 ]. Therefore, the discovery of DDRs as collagen receptors represents a new target in the regulation of tumor progression [ 84 , 85 , 86 , 87 , 88 , 89 ].…”

Section: Role Of Ddr In Cancermentioning

confidence: 99%

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

Elkamhawy

Nada

et al. 2021

IJMS

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Discoidin domain receptor (DDR) is a collagen-activated receptor tyrosine kinase that plays critical roles in regulating essential cellular processes such as morphogenesis, differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. As a result, DDR dysregulation has been attributed to a variety of human cancer disorders, for instance, non-small-cell lung carcinoma (NSCLC), ovarian cancer, glioblastoma, and breast cancer, in addition to some inflammatory and neurodegenerative disorders. Since the target identification in the early 1990s to date, a lot of efforts have been devoted to the development of DDR inhibitors. From a medicinal chemistry perspective, we attempted to reveal the progress in the development of the most promising DDR1 and DDR2 small molecule inhibitors covering their design approaches, structure-activity relationship (SAR), biological activity, and selectivity.

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Section: Role Of Ddr In Cancermentioning

confidence: 99%

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

Elkamhawy

Nada

et al. 2021

IJMS

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“…We found inhibition of DDR1/BCR signaling with EGFR/ERBB2 to be effective independent of KRAS mutation type and status in COAD and additional primary tumor model of GBM. Independent groups have reported DDR1 as a potential therapeutic candidate in KRAS-driven tumors ( 66 , 66 , 120 ), and combinatorial targeting of DDR1 has also been shown to be efficacious in KRAS-mutant tumors, lung adenocarcinoma ( 67 ), and recently pancreatic adenocarcinoma ( 121 ). We show for the first time a comprehensive investigation on identifying targeted therapies against cetuximab-resistant stem-like KRAS-driven tumors by exploring the inhibitors against a wide spectrum of signaling pathways and revealing the complementation of DDR1/BCR-ABL axis with EGFR-ERBB2, which could be harnessed to combat chemoradioresistance mediated by high β-catenin and activated KRAS.…”

Section: Discussionmentioning

confidence: 99%

“…Studies show the potential of targeting phosphatases (such as PTPN11 (SHP2) or downstream targets of PIK3/AKT like mTOR, and research to identify novel action targets is increasingly gaining attention ( 57 – 65 ). For instance, DDR1, discoidin domain receptor 1, a receptor for collagens in the extracellular matrix (ECM) of tumors has recently emerged as a potentially targetable gene against KRAS-mutant lung adenocarcinoma, and DDR1 targeting has also been identified to be beneficial against metastatic colon cancers ( 66 – 68 ). We here performed an unbiased drug screen for signaling pathways documented to be contributors to CRC ( 61 – 65 ), with an aim to identify novel drug combinations with EGFR-small-molecule inhibitors that could offer a therapeutic advantage against KRAS-driven cancers and overcome acquired radioresistance and cetuximab resistance mediated by stem-like (WNT activated) and KRAS mutation phenotype utilizing tumoroid models of COAD.…”

Section: Introductionmentioning

confidence: 99%

Identification of Synergistic Drug Combinations to Target KRAS-Driven Chemoradioresistant Cancers Utilizing Tumoroid Models of Colorectal Adenocarcinoma and Recurrent Glioblastoma

et al. 2022

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Treatment resistance is observed in all advanced cancers. Colorectal cancer (CRC) presenting as colorectal adenocarcinoma (COAD) is the second leading cause of cancer deaths worldwide. Multimodality treatment includes surgery, chemotherapy, and targeted therapies with selective utilization of immunotherapy and radiation therapy. Despite the early success of anti-epidermal growth factor receptor (anti-EGFR) therapy, treatment resistance is common and often driven by mutations in APC, KRAS, RAF, and PI3K/mTOR and positive feedback between activated KRAS and WNT effectors. Challenges in the direct targeting of WNT regulators and KRAS have caused alternative actionable targets to gain recent attention. Utilizing an unbiased drug screen, we identified combinatorial targeting of DDR1/BCR-ABL signaling axis with small-molecule inhibitors of EGFR-ERBB2 to be potentially cytotoxic against multicellular spheroids obtained from WNT-activated and KRAS-mutant COAD lines (HCT116, DLD1, and SW480) independent of their KRAS mutation type. Based on the data-driven approach using available patient datasets (The Cancer Genome Atlas (TCGA)), we constructed transcriptomic correlations between gene DDR1, with an expression of genes for EGFR, ERBB2-4, mitogen-activated protein kinase (MAPK) pathway intermediates, BCR, and ABL and genes for cancer stem cell reactivation, cell polarity, and adhesion; we identified a positive association of DDR1 with EGFR, ERBB2, BRAF, SOX9, and VANGL2 in Pan-Cancer. The evaluation of the pathway network using the STRING database and Pathway Commons database revealed DDR1 protein to relay its signaling via adaptor proteins (SHC1, GRB2, and SOS1) and BCR axis to contribute to the KRAS-PI3K-AKT signaling cascade, which was confirmed by Western blotting. We further confirmed the cytotoxic potential of our lead combination involving EGFR/ERBB2 inhibitor (lapatinib) with DDR1/BCR-ABL inhibitor (nilotinib) in radioresistant spheroids of HCT116 (COAD) and, in an additional devastating primary cancer model, glioblastoma (GBM). GBMs overexpress DDR1 and share some common genomic features with COAD like EGFR amplification and WNT activation. Moreover, genetic alterations in genes like NF1 make GBMs have an intrinsically high KRAS activity. We show the combination of nilotinib plus lapatinib to exhibit more potent cytotoxic efficacy than either of the drugs administered alone in tumoroids of patient-derived recurrent GBMs. Collectively, our findings suggest that combinatorial targeting of DDR1/BCR-ABL with EGFR-ERBB2 signaling may offer a therapeutic strategy against stem-like KRAS-driven chemoradioresistant tumors of COAD and GBM, widening the window for its applications in mainstream cancer therapeutics.

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“…They can inhibit the enzyme activity with IC 50 (Half-maximal inhibitory concentration) values of 6.8 and 7.0 nM, respectively [ 57 ]. In vitro and in vivo studies have shown 7rh effectiveness for pancreatic [ 143 ], gastric [ 72 ], and lung [ 144 ] cancers. KST9046, with a quinazoline urea scaffold, and 8v, a 3′-(imidazo[1,2-a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamide compound, were designed and optimized to inhibit DDR1 [ 145 , 146 ].…”

Section: Cancer Treatmentmentioning

confidence: 99%

“…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 ].…”

Section: Cancer Treatmentmentioning

confidence: 99%

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

Majo

Auguste

2021

Cancers

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The tumor microenvironment is a complex structure composed of the extracellular matrix (ECM) and nontumoral cells (notably cancer-associated fibroblasts (CAFs) and immune cells). Collagens are the main components of the ECM and they are extensively remodeled during tumor progression. Some collagens are ligands for the discoidin domain receptor tyrosine kinases, DDR1 and DDR2. DDRs are involved in different stages of tumor development and metastasis formation. In this review, we present the different roles of DDRs in these processes and discuss controversial findings. We conclude by describing emerging DDR inhibitory strategies, which could be used as new alternatives for the treatment of patients.

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Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma

Cited by 17 publications

References 50 publications

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

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

Identification of Synergistic Drug Combinations to Target KRAS-Driven Chemoradioresistant Cancers Utilizing Tumoroid Models of Colorectal Adenocarcinoma and Recurrent Glioblastoma

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

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