Inducing and exploiting vulnerabilities for the treatment of liver cancer

Wang, Cun; Vegna, Serena; Jin, Haojie; Benedict, Bente; Lieftink, Cor; Ramirez, Christel; Oliveira, Rodrigo Leite de; Morris, Ben; Gadiot, Jules; Wang, Wei; Chatinier, Aimée du; Wang, Liqin; Gao, Dongmei; Evers, Bastiaan; Jin, Guang‐Zhi; Zhou, Xue; Schepers, Arnout; Jochems, Fleur; Sanchez, Antonio Mulero; Mainardi, Sara; Riele, Hein te; Beijersbergen, Roderick L.; Qin, Wenxin; Akkari, Leila; Bernards, René

doi:10.1038/s41586-019-1607-3

Cited by 279 publications

(239 citation statements)

References 28 publications

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“…An early observation from these targeted genetically engineered mouse models is that therapeutic responses may be dependent upon the genetic makeup of a tumour. [110][111][112] Whether or not these will be applicable to human HCC subtypes based on the mutational drivers remains to be seen. However, it is promising that the lack of responsiveness to immunotherapy observed in murine tumours models driven by b-catenin mutations 111 is also reported in some relatively early observational studies in man.…”

Section: Key Pointmentioning

confidence: 99%

The landscape of gene mutations in cirrhosis and hepatocellular carcinoma

Müller

Bird

Nault

2020

Journal of Hepatology

117

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Chronic liver disease and primary liver cancer are a massive global problem, with a future increase in incidences predicted. The most prevalent form of primary liver cancer, hepatocellular carcinoma, occurs after years of chronic liver disease. Mutations in the genome are a causative and defining feature of all cancers. Chronic liver disease, mostly at the cirrhotic stage, causes the accumulation of progressive mutations which can drive cancer development. Within the liver, a Darwinian process selects out dominant clones with selected driver mutations but also leaves a trail of passenger mutations which can be used to track the evolution of a tumour. Understanding what causes specific mutations and how they combine with one another to form cancer is a question at the heart of understanding, preventing and tackling liver cancer. Herein, we review the landscape of gene mutations in cirrhosis, especially those paving the way toward hepatocellular carcinoma development, that have been characterised by recent studies capitalising on technological advances in genomic sequencing. With these insights, we are beginning to understand how cancers form in the liver, particularly on the background of chronic liver disease. This knowledge may soon lead to breakthroughs in the way we detect, diagnose and treat this devastating disease.

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Section: Key Pointmentioning

confidence: 99%

The landscape of gene mutations in cirrhosis and hepatocellular carcinoma

Müller

Bird

Nault

2020

Journal of Hepatology

117

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“…In this approach, the first drug induces cell vulnerability (senescence in this case), which is exploited by the second agent. In liver cancer, Wang et al [99] have shown that the TOR-KI AZD8055 [100] exhibits a greater activity in senescent cells as compared with proliferating cells. In this setting, XL413 acted as a second hit to inhibit the DNA-replication kinase CDC7, which selectively induces senescence in liver cancer cells with mutations in TP53 or its upstream regulators.…”

Section: Combination Of Mtor Inhibitors In Hccmentioning

confidence: 99%

Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma

Ferrín

Guerrero

Amado

et al. 2020

IJMS

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Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and occurs mainly in patients with liver cirrhosis. The mammalian target of rapamycin (mTOR) signaling pathway is involved in many hallmarks of cancer including cell growth, metabolism re-programming, proliferation and inhibition of apoptosis. The mTOR pathway is upregulated in HCC tissue samples as compared with the surrounding liver cirrhotic tissue. In addition, the activation of mTOR is more intense in the tumor edge, thus reinforcing its role in HCC proliferation and spreading. The inhibition of the mTOR pathway by currently available pharmacological compounds (i.e., sirolimus or everolimus) is able to hamper tumor progression both in vitro and in animal models. The use of mTOR inhibitors alone or in combination with other therapies is a very attractive approach, which has been extensively investigated in humans. However, results are contradictory and there is no solid evidence suggesting a true benefit in clinical practice. As a result, neither sirolimus nor everolimus are currently approved to treat HCC or to prevent tumor recurrence after curative surgery. In the present comprehensive review, we analyzed the most recent scientific evidence while providing some insights to understand the gap between experimental and clinical studies.

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“…This is one of a series of papers in which Rene Bernards and colleagues reveal the potential of CRISPR screens for discovering therapeutic targets in HCC 5 8–11. In line with Zender’s shRNA screen, one of these papers confirmed that combining sorafenib with MEK inhibition could be beneficial in some HCCs 10.…”

mentioning

confidence: 76%