AXL and Resistance to Cetuximab

In this study, we show that overexpression of the oncogenic receptor tyrosine kinase AXL is sufficient to mediate acquired resistance to cetuximab in models of non–small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), where AXL was overexpressed, activated, and tightly associated with EGFR expression in cells resistant to cetuximab (CtxR cells). Using RNAi methods and novel AXL-targeting agents, we found that AXL activation stimulated cell proliferation, EGFR activation, and MAPK signaling in CtxR cells. Notably, EGFR directly regulated the expression of AXL mRNA through MAPK signaling and the transcription factor c-Jun in CtxR cells, creating a positive feedback loop that maintained EGFR activation by AXL. Cetuximab-sensitive parental cells were rendered resistant to cetuximab by stable overexpression of AXL or stimulation with EGFR ligands, the latter of which increased AXL activity and association with the EGFR. In tumor xenograft models, the development of resistance following prolonged treatment with cetuximab was associated with AXL hyperactivation and EGFR association. Furthermore, in an examination of patient-derived xenografts established from surgically resected HNSCCs, AXL was overexpressed and activated in tumors that displayed intrinsic resistance to cetuximab. Collectively, our results identify AXL as a key mediator of cetuximab resistance, providing a rationale for clinical evaluation of AXL-targeting drugs to treat cetuximab-r...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Therapeutics, Targets, and Chemical Biology Source Type: research

Related Links:

Abstract Myoferlin, a protein of the ferlin family, has seven C2 domains and exhibits activity in some cells, including myoblasts and endothelial cells. Recently, myoferlin was identified as a promising target and biomarker in non-small-cell lung cancer, breast cancer, pancreatic adenocarcinoma, hepatocellular carcinoma, colon cancer, melanoma, oropharyngeal squamous cell carcinoma, head and neck squamous cell carcinoma, clear cell renal cell carcinoma and endometrioid carcinoma. This evidence indicated that myoferlin was involved in the proliferation, invasion and migration of tumour cells, the mechanism of which...
Source: J Cell Mol Med - Category: Molecular Biology Authors: Tags: J Cell Mol Med Source Type: research
Abstract MicroRNAs (miRNAs) are short single-stranded RNAs, measuring 21 to 23 nucleotides in length and regulate gene expression at the post-transcriptional level through mRNA destabilization or repressing protein synthesis. Dysregulation of miRNAs can lead to tumorigenesis through changes in regulation of key cellular processes such as cell proliferation, cell survival, and apoptosis. miR-125a-5p has been implicated as a tumor suppressor miRNA in malignancies such as non-small cell lung cancer and colon cancer. However, the role of miR-125a-5p has not been fully investigated in head and neck squamous cell carcin...
Source: Neoplasia - Category: Cancer & Oncology Authors: Tags: Neoplasia Source Type: research
Conclusion: IOV in target volume delineation increases during treatment, where a disparity in institutional adaptation practices adds to the conventional causes of IOV. Consensus guidelines are urgently needed. PMID: 31271079 [PubMed - as supplied by publisher]
Source: Acta Oncologica - Category: Cancer & Oncology Authors: Tags: Acta Oncol Source Type: research
Cancers, Vol. 11, Pages 765: α11β1 Integrin is Induced in a Subset of Cancer-Associated Fibroblasts in Desmoplastic Tumor Stroma and Mediates In Vitro Cell Migration Cancers doi: 10.3390/cancers11060765 Authors: Zeltz Alam Liu Erusappan Hoschuetzky Molven Parajuli Cukierman Costea Lu Gullberg Integrin α11β1 is a collagen receptor that has been reported to be overexpressed in the stroma of non-small cell lung cancer (NSCLC) and of head and neck squamous cell carcinoma (HNSCC). In the current study, we further analyzed integrin α11 expression in 1...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Discussion MDSCs violently emerge in pathological conditions in an attempt to limit potentially harmful immune and inflammatory responses. Mechanisms supporting their expansion and survival are deeply investigated in cancer, in the perspective to reactivate specific antitumor responses and prevent their contribution to disease evolution. These findings will likely contribute to improve the targeting of MDSCs in anticancer immunotherapies, either alone or in combination with immune checkpoint inhibitors. New evidence indicates that the expansion of myeloid cell differentiation in pathology is subject to fine-tuning, as its...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Conclusion MTDH is pro-oncogenic factor playing multifaceted and diverse roles in cancer progression. Its association and central role in regulating signaling pathways such a MAPK, wnt/β-catenin, PI3K/AkT, NF-κβ pathways in various cancers shows that it plays a vital role in metastasis. MTDH contribution to chemo and radiotherapy resistance provides a new direction for the development of anticancer therapeutics. Multiple mechanisms converge to promote expression of MTDH in cancers. Further studies are therefore warranted to determine whether the elevated MTDH expression has prognostic value for development...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
In this study, to improve our understanding of the role of ATP1A1 in the malignant phenotype and pathogenesis of GSCs, we evaluated ATP1A1 expression in GBMs of different grades and in two primary GSC lines established from human GBM tissues. We evaluated the role of ATP1A1 in GSC growth, its interactions with Src, and the activation of the ERK1/2 and AKT pathways. Our results revealed that ATP1A1 acts as an oncogene in our GSC models and targeting ATP1A1/Src may suppress GSC proliferation and growth. Materials and Methods Cell Isolation and Culture Human brain GBM tissues were from pathologically confirmed surgical spe...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusions: In OSCC, very low preoperative NLR values have a negative prognostic impact on survival and recurrence, similarly to high ratios. ENE and perineural spread are the most important clinical-pathologic prognosticators. Introduction Oral squamous cell carcinoma (OSCC) accounts for more than 95% of oral tumors and is the eighth most frequent cancer worldwide, with an estimated incidence of 640,000 new cases per year (1). Survival of OSCC has slightly improved over the last 30 years, probably as a consequence of multimodal treatment spreading. However, intensified therapeutic regimens can result in signific...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Laia Gorchs1*, Carlos Fernández Moro1,2, Peter Bankhead3, Katharina P. Kern1, Imrul Sadeak1, Qingda Meng1, Elena Rangelova4,5 and Helen Kaipe1,6* 1Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden 2Department of Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden 3Division of Pathology, Centre for Genomic &Experimental Medicine, Western General Hospital, Institute of Genetics &Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom 4Department of CLINTEC, Karolinska Institutet, Stockholm, Sweden 5Pancreatic Surgery Unit, Center for Digesti...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Conclusions MDSC are major players in the immunosuppressive scenario in cancer, thanks to their phenotype heterogeneity and critical interaction with several innate immune cells, thus representing a crucial target in oncology. Here we reviewed the interactions of MDSCs with NK cells. The contribution of key cytokines, chemokines and mediators active in this process have been discussed. We also described the contribution of MDSC on angiogenesis directly or indirectly through interactions with NK and immunosuppressive activities. A parallel of the cancer associated to the decidual counterpart of these cells is discussed, a...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
More News: Biology | Cancer | Cancer & Oncology | Carcinoma | Chemistry | Erbitux | HNSCC | Lung Cancer | Non-Small Cell Lung Cancer | Skin Cancer | Squamous Cell Carcinoma | Study