A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer

Kim, Richard; Tan, Elaine; Wang, Emily; Mahipal, Amit; Chen, Dung Tsa; Cao, Biwei; Masawi, Fadzai; Machado, Cindy; Yu, James; Kim, Dae Won

doi:10.1634/theoncologist.2020-0759

Cited by 20 publications

(13 citation statements)

References 15 publications

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“…3C-E). Interestingly, there are indeed some reports on the synergistic application of above inhibitors and other anticancer drugs for the treatment of HCC [46][47][48][49], which supported the original intention of our study, i.e., to find key TME-related targets for the combination targeted therapy. Collectively, we confirmed that the integrin-FAK-Src, MEK-ERK, and PI3K-AKT pathways were involved in microstructure formation.…”

Section: Hiis Activated Integrin-α 5 β 1 Downstream Signalingsupporting

confidence: 83%

The interactions between integrin α₅β₁ of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis

Peng¹,

Hao²,

Tong³

et al. 2022

Int. J. Biol. Sci.

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Hepatocellular carcinoma (HCC) progression is closely related to pathological fibrosis, which involves heterotypic intercellular interactions (HIIs) between liver cancer cells and fibroblasts. Here, we studied them in a direct coculture model, and identified fibronectin from fibroblasts and integrin-α 5 β 1 from liver cancer cells as the primary responsible molecules utilizing CRISPR/Cas9 gene-editing technology. Coculture led to the formation of 3D multilayer microstructures, and obvious fibronectin remodeling was caused by upregulated integrin-α 5 β 1 , which greatly promoted cell growth in 3D microstructures. Integrin-α 5 was more sensitive and specific than integrin-β 1 in this process. Subsequent mechanistic exploration revealed the activation of integrin-Src-FAK, AKT and ERK signaling pathways. Importantly, the growth-promoting effect of HIIs was verified in a xenograft tumor model, in which more blood vessels were observed in bigger tumors derived from the coculture group than that derived from monocultured groups. Hence, we conducted triculture by introducing human umbilical vein endothelial cells, which aligned to and differentiated along multilayer microstructures in an integrin-α 5 β 1 dependent manner. Furthermore, fibronectin, integrin-α 5 , and integrin-β 1 were upregulated in 52 HCC tumors, and fibronectin was related to microvascular invasion. Our findings identify fibronectin, integrin-α 5 , and integrin-β 1 as tumor microenvironment-related targets and provide a basis for combination targeted therapeutic strategies for future HCC treatment.

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Section: Hiis Activated Integrin-α 5 β 1 Downstream Signalingsupporting

confidence: 83%

The interactions between integrin α₅β₁ of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis

Peng¹,

Hao²,

Tong³

et al. 2022

Int. J. Biol. Sci.

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“…Thus, ferroptosis likely plays an important role in the occurrence and development of HCC. 186,187 According to recent studies, the effect of the p62-Keap1-NRF2 signaling pathway on HCC is closely related to ferroptosis induced by elastin/sorafenib. Interference with p62 (the substrate adaptor) enhances ferroptosis induced by erastin/sorafenib in HCC cells.…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

Emerging mechanisms and targeted therapy of ferroptosis in cancer

et al. 2021

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“…[115][116][117][118][119] However, the efficacy of combination therapy is not supported by all studies. 120 Clinical trials demonstrated that the MEK inhibitor, trametinib, combined with the multitargeted TKI midostaurin can improve the prognosis of patients with FLT3-TKI-resistant AML. 121 In addition, P21 (RAC1)-activated kinase 2 (PAK), whose overexpression is related to lenvatinib resistance in some types of TC is also a downstream molecule of RAS.…”

Section: Mechanisms Of Tki Resistancementioning

confidence: 99%

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

Yang

Wang

et al. 2022

Sig Transduct Target Ther

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Protein tyrosine kinases (PTKs) are a class of proteins with tyrosine kinase activity that phosphorylate tyrosine residues of critical molecules in signaling pathways. Their basal function is essential for maintaining normal cell growth and differentiation. However, aberrant activation of PTKs caused by various factors can deviate cell function from the expected trajectory to an abnormal growth state, leading to carcinogenesis. Inhibiting the aberrant PTK function could inhibit tumor growth. Therefore, tyrosine kinase inhibitors (TKIs), target-specific inhibitors of PTKs, have been used in treating malignant tumors and play a significant role in targeted therapy of cancer. Currently, drug resistance is the main reason for limiting TKIs efficacy of cancer. The increasing studies indicated that tumor microenvironment, cell death resistance, tumor metabolism, epigenetic modification and abnormal metabolism of TKIs were deeply involved in tumor development and TKI resistance, besides the abnormal activation of PTK-related signaling pathways involved in gene mutations. Accordingly, it is of great significance to study the underlying mechanisms of TKIs resistance and find solutions to reverse TKIs resistance for improving TKIs efficacy of cancer. Herein, we reviewed the drug resistance mechanisms of TKIs and the potential approaches to overcome TKI resistance, aiming to provide a theoretical basis for improving the efficacy of TKIs.

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A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer

Cited by 20 publications

References 15 publications

The interactions between integrin α₅β₁ of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis

The interactions between integrin α₅β₁ of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis

Emerging mechanisms and targeted therapy of ferroptosis in cancer

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

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A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer

Cited by 20 publications

References 15 publications

The interactions between integrin α5β1 of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis

The interactions between integrin α5β1 of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis

Emerging mechanisms and targeted therapy of ferroptosis in cancer

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

Contact Info

Product

Resources

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The interactions between integrin α₅β₁ of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis

The interactions between integrin α₅β₁ of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis