Pericytes Elicit Resistance to Vemurafenib and Sorafenib Therapy in Thyroid Carcinoma via the TSP-1/TGFβ1 Axis

Prete, Alessandro; Lo, Agnes S.; Sadow, Peter M.; Bhasin, Swati S.; Antonello, Zeus A.; Vodopivec, Danica M.; Ullas, Soumya; Sims, Jennifer N.; Clohessy, John G.; Dvorak, Ann M.; Sciuto, Tracey E.; Bhasin, Manoj; Murphy-Ullrich, Joanne E.; Lawler, Jack; Karumanchi, S. Ananth; Nucera, Carmelo

doi:10.1158/1078-0432.ccr-18-0693

Cited by 44 publications

(28 citation statements)

References 56 publications

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“…However, CRC-based evidence for c-MET and VEGF dual targeting remains rare, and a study on NSCLC stated no better effect by combined blocking. 229 A number of studies found factors such as a high level of TGFβ, 230,231 upregulation of IL-1, 231 downregulation of MIF (macrophage migration inhibitory factor), 232 and overexpression of PDGFR 233 in a wide range of VEGF-blockade-resistant cancers, implying possible connections to antiangiogenic therapeutic resistance; however, a lack of adequate data on silencing these factors in clinical cases has limited their further confirmation for CRC therapy.…”

Section: Targeting Angiogenesismentioning

confidence: 99%

Comprehensive review of targeted therapy for colorectal cancer

Xie

Chen

Fang

2020

Sig Transduct Target Ther

908

657

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Colorectal cancer (CRC) is among the most lethal and prevalent malignancies in the world and was responsible for nearly 881,000 cancer-related deaths in 2018. Surgery and chemotherapy have long been the first choices for cancer patients. However, the prognosis of CRC has never been satisfying, especially for patients with metastatic lesions. Targeted therapy is a new optional approach that has successfully prolonged overall survival for CRC patients. Following successes with the anti-EGFR (epidermal growth factor receptor) agent cetuximab and the anti-angiogenesis agent bevacizumab, new agents blocking different critical pathways as well as immune checkpoints are emerging at an unprecedented rate. Guidelines worldwide are currently updating the recommended targeted drugs on the basis of the increasing number of high-quality clinical trials. This review provides an overview of existing CRC-targeted agents and their underlying mechanisms, as well as a discussion of their limitations and future trends.

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Section: Targeting Angiogenesismentioning

confidence: 99%

Comprehensive review of targeted therapy for colorectal cancer

Xie

Chen

Fang

2020

Sig Transduct Target Ther

908

657

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“…Interestingly, the TME can itself modify the signaling of neoplastic cells and drive resistance to RTKIs. In thyroid carcinoma, pericytes lead to vemurafenib resistance through secretion of thrombospondine 1 (TSP-1) and transforming growth factor beta-1 (TGFβ1), which increase expression of protein kinase R (PKR)-like endoplasmic reticulum kinase (pERK1/2), phosphorylated AKT (pAKT), and phosphorylated mothers against decapentaplegic homolog 3 (pSMAD3) levels [66]. Similarly, stromal cells can secrete hepatocyte growth factor (HGF) which activates MET that in turn stimulates MAPK and Pi3K/AKT/mTOR, leading to BRAFi resistance of melanoma cells [67,68].…”

Section: Impact Of the Non-immune Microenvironment On Receptor Tyrosimentioning

confidence: 99%

Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy

Pottier

Fresnais

Gilon

et al. 2020

Cancers

289

191

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Receptor tyrosine kinases (RTKs) are key regulatory signaling proteins governing cancer cell growth and metastasis. During the last two decades, several molecules targeting RTKs were used in oncology as a first or second line therapy in different types of cancer. However, their effectiveness is limited by the appearance of resistance or adverse effects. In this review, we summarize the main features of RTKs and their inhibitors (RTKIs), their current use in oncology, and mechanisms of resistance. We also describe the technological advances of artificial intelligence, chemoproteomics, and microfluidics in elaborating powerful strategies that could be used in providing more efficient and selective small molecules inhibitors of RTKs. Finally, we discuss the interest of therapeutic combination of different RTKIs or with other molecules for personalized treatments, and the challenge for effective combination with less toxic and off-target effects.

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“…vemurafenib) and tyrosine kinases (TKs) (i.e. sorafenib) via TSP-1/TGFβ1 axis 35 (Figure 1). Specifically, pericytes were able to secrete both TSP-1 and TGFβ1, triggering drug resistance.…”

Section: Genetic Alterations In Early Thyroid Tumorigenesismentioning

confidence: 99%

“…BRAF WT/V600E -PTC clinical samples were enriched in pericytes, and TSP-1 and TGFβ1 expression evoked gene-regulatory networks and pathways in the microenvironment essential for BRAF V600E -PTC cell survival. Critically, antagonism of the TSP-1/TGFβ1 axis reduced tumor cell growth and overcomes drug resistance 35 . Antagonizing this molecular pathway may represent a novel therapeutic translational approach against BRAF WT/V600E -PTC resistant to targeted therapies.…”

Section: Genetic Alterations In Early Thyroid Tumorigenesismentioning

confidence: 99%

Coding Molecular Determinants of Thyroid Cancer Development and Progression

Valvo

Nucera

2019

Endocrinology and Metabolism Clinics of North America

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Thyroid cancer is the most common endocrine malignancy and its trends of incidence are the highest compared to other tumors. The characterization of the molecular pathways involved in thyroid cancer initiation and progression has made huge progress, underlining the essential role of determined signaling to promote specific features, including dedifferentiation, invasiveness, metastasis and drug resistance. The discovery of many genetic alterations that include point mutations, chromosome translocations, deletions, and copy-number gain has provided new exciting biological insights with translational/clinical applications. Furthermore, mechanisms of drug resistance involve role of pericytes and deregulation of pro-angiogenic molecules such as the tyrosine kinases (TKs) in the microenvironment. BRAF V600E-positive thyroid tumor growth is also influenced by the tumor microenvironment, which is in turn altered by the tumor itself, leading to abnormal extracellular matrix (ECM) deposition and activation of angiogenic pathways. Many of the processes involved in thyroid tumor growth and metastasis are mediated by signaling molecules downstream of BRAF V600E and activated TKs. Overall, understanding how molecular pathways interplay is one of the key-strategies to develop new therapeutic treatments and improve prognosis.

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Pericytes Elicit Resistance to Vemurafenib and Sorafenib Therapy in Thyroid Carcinoma via the TSP-1/TGFβ1 Axis

Abstract: Pericytes shield BRAF-PTC cells from targeted therapy via TSP-1 and TGFβ1, suggesting this axis as a new therapeutic target for overcoming resistance to BRAF and TK inhibitors.

Cited by 44 publications

References 56 publications

Comprehensive review of targeted therapy for colorectal cancer

Comprehensive review of targeted therapy for colorectal cancer

Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy

Coding Molecular Determinants of Thyroid Cancer Development and Progression

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