scholarly journals Acquired resistance to BRAF inhibition induces epithelial-to-mesenchymal transition in BRAF (V600E) mutant thyroid cancer by c-Met-mediated AKT activation

Oncotarget ◽  
2016 ◽  
Vol 8 (1) ◽  
pp. 596-609 ◽  
Author(s):  
Hyung Kwon Byeon ◽  
Hwi Jung Na ◽  
Yeon Ju Yang ◽  
Sooah Ko ◽  
Sun Och Yoon ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Acquired Resistance ◽  
Braf V600e ◽  
Mesenchymal Transition ◽  
Akt Activation ◽  
Braf Inhibition

scholarly journals Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Steven M. Bray ◽  
Jeeyun Lee ◽  
Seung Tae Kim ◽  
Joon Young Hur ◽  
Philip J. Ebert ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Acquired Resistance ◽  
Genomic Analysis ◽  
Braf V600e ◽  
Intrinsic Resistance ◽  
Mtor Inhibition ◽  
Mesenchymal Transition ◽  
Colorectal Cancer Patients

Abstract Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4–RET and LMNA–NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.

scholarly journals Lessons to Learn for Adequate Targeted Therapy Development in Metastatic Colorectal Cancer Patients

2021 ◽  
Vol 22 (9) ◽  
pp. 5019
Author(s):  
Helena Oliveres ◽  
David Pesántez ◽  
Joan Maurel
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Tyrosine Kinases ◽  
Epithelial To Mesenchymal Transition ◽  
Acquired Resistance ◽  
Post Translational Modification ◽  
Mesenchymal Transition ◽  
Igf1r Signaling ◽  
Colorectal Cancer Patients

Insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase that regulates cell growth and proliferation. Upregulation of the IGF1R pathway constitutes a common paradigm shared with other receptor tyrosine kinases such as EGFR, HER2, and MET in different cancer types, including colon cancer. The main IGF1R signaling pathways are PI3K-AKT and MAPK-MEK. However, different processes, such as post-translational modification (SUMOylation), epithelial-to-mesenchymal transition (EMT), and microenvironment complexity, can also contribute to intrinsic and acquired resistance. Here, we discuss new strategies for adequate drug development in metastatic colorectal cancer patients.

scholarly journals Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5081
Author(s):  
Yuta Adachi ◽  
Ryo Kimura ◽  
Kentaro Hirade ◽  
Hiromichi Ebi
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Acquired Resistance ◽  
Metabolic Reprogramming ◽  
Mesenchymal Transition ◽  
Cellular Processes ◽  
Activating Mutations ◽  
Survival Signaling ◽  
Kras Protein ◽  
Effector Pathways ◽  
Specific Inhibitors

Activating mutations in KRAS are present in 25% of human cancers. When mutated, the KRAS protein becomes constitutively active, stimulating various effector pathways and leading to the deregulation of key cellular processes, including the suppression of apoptosis and enhancement of proliferation. Furthermore, mutant KRAS also promotes metabolic deregulation and alterations in the tumor microenvironment. However, some KRAS mutant cancer cells become independent of KRAS for their survival by activating diverse bypass networks that maintain essential survival signaling originally governed by mutant KRAS. The proposed inducers of KRAS independency are the activation of YAP1 and/or RSK-mTOR pathways and co-mutations in SKT11 (LKB1), KEAP1, and NFE2L2 (NRF2) genes. Metabolic reprogramming, such as increased glutaminolysis, is also associated with KRAS autonomy. The presence or absence of KRAS dependency is related to the heterogeneity of KRAS mutant cancers. Epithelial-to-mesenchymal transition (EMT) in tumor cells is also a characteristic phenotype of KRAS independency. Translationally, this loss of dependence is a cause of primary and acquired resistance to mutant KRAS-specific inhibitors. While KRAS-dependent tumors can be treated with mutant KRAS inhibitor monotherapy, for KRAS-independent tumors, we need an improved understanding of activated bypass signaling pathways towards leveraging vulnerabilities, and advancing therapeutic options for this patient subset.

scholarly journals DDR1 regulates thyroid cancer cell differentiation via IGF-2/IR-A autocrine signaling loop

2019 ◽  
Vol 26 (1) ◽  
pp. 197-214 ◽  
Author(s):  
Veronica Vella ◽  
Maria Luisa Nicolosi ◽  
Patrizia Cantafio ◽  
Michele Massimino ◽  
Rosamaria Lappano ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Differentiation ◽  
Epithelial To Mesenchymal Transition ◽  
Human Thyroid ◽  
Autocrine Signaling ◽  
Differentiation Markers ◽  
Autocrine Loop ◽  
Mesenchymal Transition ◽  
Poorly Differentiated ◽  
Induced Changes

Patients with thyroid cancers refractory to radioiodine (RAI) treatment show a limited response to various therapeutic options and a low survival rate. The recent use of multikinase inhibitors has also met limited success. An alternative approach relies on drugs that induce cell differentiation, as the ensuing increased expression of the cotransporter for sodium and iodine (NIS) may partially restore sensitivity to radioiodine. The inhibition of the ERK1/2 pathway has shown some efficacy in this context. Aggressive thyroid tumors overexpress the isoform-A of the insulin receptor (IR-A) and its ligand IGF-2; this IGF-2/IR-A loop is associated with de-differentiation and stem-like phenotype, resembling RAI-refractory tumors. Importantly, IR-A has been shown to be positively modulated by the non-integrin collagen receptor DDR1 in human breast cancer. Using undifferentiated human thyroid cancer cells, we now evaluated the effects of DDR1 on IGF-2/IR-A loop and on markers of cell differentiation and stemness. DDR1 silencing or downregulation caused significant reduction of IR-A and IGF-2 expression, and concomitant increased levels of differentiation markers (NIS, Tg, TSH, TPO). Conversely, markers of epithelial-to-mesenchymal transition (Vimentin, Snail-2, Zeb1, Zeb2 and N-Cadherin) and stemness (OCT-4, SOX-2, ABCG2 and Nanog) decreased. These effects were collagen independent. In contrast, overexpression of either DDR1 or its kinase-inactive variant K618A DDR1-induced changes suggestive of less differentiated and stem-like phenotype. Collagen stimulation was uneffective. In conclusion, in poorly differentiated thyroid cancer, DDR1 silencing or downregulation blocks the IGF-2/IR-A autocrine loop and induces cellular differentiation. These results may open novel therapeutic approaches for thyroid cancer.

scholarly journals P4HA2 Promotes Epithelial-to-Mesenchymal Transition and Glioma Malignancy through the Collagen-Dependent PI3K/AKT Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Jing Lin ◽  
Lei Jiang ◽  
Xiaogang Wang ◽  
Wenxin Wei ◽  
Chaoli Song ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Enzyme Inhibitor ◽  
Tumor Xenograft ◽  
Mesenchymal Transition ◽  
Akt Activation ◽  
Collagen Genes ◽  
First Time

Prolyl-4-hydroxylase subunit 2 (P4HA2) is a member of collagen modification enzymes involved in the remodeling of the extracellular matrix (ECM). Mounting evidence has suggested that deregulation of P4HA2 is common in cancer. However, the role of P4HA2 in glioma remains unknown. The present study aimed to elucidate the expression pattern, oncogenic functions, and molecular mechanisms of P4HA2 in glioblastoma cells. The TCGA datasets and paraffin samples were used for examining the expressions of P4HA2. P4HA2-specific lentivirus was generated to assess its oncogenic functions. A P4HA2 enzyme inhibitor (DHB) and an AKT agonist (SC79) were utilized to study the mechanisms. As a result, we demonstrated that P4HA2 is overexpressed in glioma and inversely correlates with patient survival. Knockdown of P4HA2 inhibited proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) like phenotype of glioma cells in vitro and suppressed tumor xenograft growth in vivo. Mechanistically, expressions of a series of collagen genes and of phosphorylated PI3K/AKT were downregulated by either P4HA2 silencing or inhibition of its prolyl hydroxylase. Finally, the inhibitory effects on the migration, invasion, and EMT-related molecules by P4HA2 knockdown were reversed by AKT activation with SC79. Our findings for the first time reveal that P4HA2 acts as an oncogenic molecule in glioma malignancy by regulating the expressions of collagens and the downstream PI3K/AKT signaling pathway.

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