Wild type Kirsten rat sarcoma is a novel microRNA-622-regulated therapeutic target for hepatocellular carcinoma and contributes to sorafenib resistance

Dietrich, Péter; Koch, Andreas; Fritz, Valerie; Hartmann, Arndt; Bosserhoff, Anja‐Katrin; Hellerbrand, Claus

doi:10.1136/gutjnl-2017-315402

Cited by 80 publications

(140 citation statements)

References 50 publications

(20 reference statements)

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“…For instance, Wu et al found that adrenergic receptorβ2 activated AKT signaling to facilitate glucose metabolism reprogramming through mediating hypoxia‐inducible factor‐1α (HIF‐1α) stabilization, which resulted in acquired sorafenib resistance both in vivo and vitro . In addition, Dietrich et al uncovered that dysregulation in the upstream mediator of PI3K/AKT, KRAS, led to sorafenib acquired resistance caused by loss of tumor suppressive microRNA‐622 . Aside from this, we previously demonstrated that the occurrence of primary resistance after temporary sorafenib stimulation was attributed to activation of AKT signaling for facilitating cell survival, indicating that the activation of AKT was not only implicated in the acquired resistance of sorafenib treatment but also highly connected to sorafenib primary resistance, which is in accordance with previous studies .…”

Section: Discussionmentioning

confidence: 86%

Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma

et al. 2018

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Hepatocellular carcinoma (HCC) is the malignancy derived from normal hepatocytes with increasing incidence and extremely poor prognosis worldwide. The only approved first‐line systematic treatment agent for HCC, sorafenib, is capable to effectively improve advanced HCC patients’ survival. However, it is gradually recognized that the therapeutic response to sorafenib could be drastically diminished after short‐term treatment, defined as primary resistance. The present study is aimed to explore the role of stress‐inducible protein Sestrin2 (SESN2), one of the most important sestrins family members, in sorafenib primary resistance. Herein, we initially found that SESN2 expression was significantly up‐regulated in both HCC cell lines and tissues compared to normal human hepatocytes and corresponding adjacent liver tissues, respectively. In addition, SESN2 expression was highly correlated with sorafenib IC50 of HCC cell lines. Thereafter, we showed that sorafenib treatment resulted in an increase of SESN2 expression and the knockdown of SESN2 exacerbated sorafenib‐induced proliferation inhibition and cell apoptosis. Further mechanistic study uncovered that SESN2 deficiency impaired both AKT and AMPK phosphorylation and activation after sorafenib treatment. Moreover, the correlations between SESN2 expression and both phosphor‐AKT and phosphor‐AMPK expression were illustrated in HCC tissues. Taken together, our study demonstrates that SESN2 activates AKT and AMPK signaling as a novel mechanism to induce sorafenib primary resistance in HCC.

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Section: Discussionmentioning

confidence: 86%

Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma

et al. 2018

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“…ncRNAs are emerging key regulators of post-transcriptional activity in cancers. miRNAs are most frequently studied and some of them have been proved to be significantly dysregulated in HCC, promoting tumor progression and sorafenib resistance [83,84]. Consistent with the idea that certain cell states determine drug sensitivity, miRNAs, as well as other ncRNAs including lncRNAs that mostly act as sponges of miRNAs, modulated sorafenib sensitivity through regulating EMT and stemness in HCC [85].…”

Section: Post-transcriptional Regulationmentioning

confidence: 87%

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

et al. 2020

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A B S T R A C TIn most cases, sorafenib-resistant HCC cells exhibit significant mesenchymal phenotype and stemness features. In this context, tumor cells might undergo cell fate transition in response to sorafenib or other targeted drugs in the presence or absence of genetic mutations. Therefore, understanding the major characteristics of drug-resistant cells state helps to discover new treatments that overcome drug resistance. To note, little is known about the metabolic or microenvironmental aspects of the certain tumor cell states beyond the genome. This review mainly focuses on the underlying mechanisms of acquired sorafenib resistance based on CSCs and EMT models, which explain tumor heterogeneity and have been considered the major cause of secondary sorafenib resistance. In particular, it discusses how the tumor microenvironment and tumor metabolism regulate cell stemness, mesenchymal state, and sorafenib resistance through epigenetic regulations, and provides reliable targets that might have synergetic effect with sorafenib.

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“…Loss of wild‐type KRAS occurs upon tumor progression due to overcoming oncogenic form of KRAS (i.e., mutant form) causing allelic imbalance (Ambrogio et al, ), so rescuing wild‐type KRAS can be therapeutic for some types of cancers. For hepatocellular carcinoma (HCC), this approach has failed because of showing a positive relation between high expression of wild‐type KARS with poor patient survival and advanced tumor size (Dietrich et al, ).…”

Section: Mapk Signalingmentioning

confidence: 99%

“…There are strong evidences for cancer type and grade dependency of MAPK mutational profile. KRAS mutation in HCC is rare, compared with other types of cancers (Dietrich et al, ), while for NSCLC this rate is high (Kitajima and Barbie, ), and it reaches to over 90% in PDAC patients (Muzumdar et al, ). Oncogenic mutations of NRAS commonly occur in myeloid leukemia (Kunimoto et al, ).…”

Section: Mutation and Activity Of Mapk Pathway Is Influenced From Canmentioning

confidence: 99%

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

Najafi

Ahmadi

Mortezaee

2019

Cell Biology International

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Mitogen-activated protein kinase (MAPK) signaling pathway is activated in a wide spectrum of human tumors, exhibiting cardinal oncogenic roles and sustained inhibition of this pathway is considered as a primary goal in clinic. Within this pathway, receptor tyrosine kinases such as epithelial growth factor receptor, mesenchymal-epithelial transition, and AXL act as upstream regulators of RAS/RAF/MEK/extracellular-signal-regulated kinase. MAPK signaling is active in both early and advanced stages of tumorigenesis, and it promotes tumor proliferation, survival, and metastasis. MAPK regulatory effects on cellular constituent of the tumor microenvironment is for immunosuppressive purposes. Cross-talking between MAPK with oncogenic signaling pathways including WNT, cyclooxygenase-2, transforming growth factor-β, NOTCH and (in particular) with phosphatidylinositol 3-kinase is contributed to the multiplication of tumor progression and drug resistance. Developing resistance (intrinsic or acquired) to MAPK-targeted therapy also occurs due to heterogeneity of tumors along with mutations and negative feedback loop of interactions exist between various kinases causing rebound activation of this signaling. Multidrug regimen is a preferred therapeutic avenue for targeting MAPK signaling. To enhance patient tolerance and to mitigate potential adversarial effects related to the combination therapy, determination of a desired dose and drug along with pre-evaluation of cancer-type-specific kinase mutation and sensitivity, especially for patients receiving triplet therapy is an urgent need.

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Wild type Kirsten rat sarcoma is a novel microRNA-622-regulated therapeutic target for hepatocellular carcinoma and contributes to sorafenib resistance

Abstract: KRAS is dysregulated in HCC by loss of tumour-suppressive microRNA-622, contributing to tumour progression, sorafenib sensitivity and resistance. KRAS inhibition alone or in combination with sorafenib appears as novel promising therapeutic strategy for HCC.

Cited by 80 publications

References 50 publications

Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma

Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

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