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Hepatocellular carcinoma (HCC) represents a serious and urgent global health problem because of its increasing incidence and the limited therapeutic options.1 2 The standard treatment for patients with advanced HCC is the multikinase inhibitor sorafenib, which shows only modest survival improvement of approximately 2–3 months and remains associated with disease progression in a large number of patients.3 4 Therefore, to improve the survival of patients with advanced HCC, it is fundamental to understand the mechanisms of sorafenib resistance.
The antitumour efficacy of sorafenib is mainly based on the inhibition of the proliferative RAF/mitogen-activated protein kinase (MAPK) pathway, which is regulated by upstream RAS proteins.5 6 The majority of human HCCs shows an activation of this pathway, which is associated with shorter survival.6–9 In contrast to other human tumours, RAS activation in HCC occurs in the absence of RAS mutation, which is rare in this tumour entity.6 10 The pathomechanisms of enhanced activation of RAS and in particular of KRAS, the most important RAS isoform for carcinogenesis, in HCC as well as its implication for sorafenib resistance remain largely unclear.
There is increasing evidence that microRNAs contribute to carcinogenesis as well as anticancer drug resistance.11 12 MicroRNAs represent short, non-coding RNAs that negatively regulate gene expression at the post-transcriptional or translational level.13 They can affect many cellular pathways such as of proliferation, differentiation, apoptosis and immune responses.14 15 Furthermore, microRNAs can act as regulators of oncogenes or tumour suppressors. For instance, it could be demonstrated that microRNA-21 downregulates the expression of the tumour suppressor gene PTEN in HCC.16 MicroRNA and target gene expression might vary in different HCC causes, and specific microRNA expression patterns in different etiologies might permit HCC development and progression. Furthermore, it has to be considered that a single microRNA can impact many targets and vice versa a single target can be affected by multiple microRNAs, which can vary with changes in disease condition and tumour microenvironment.11 17
In Gut, Dietrich et al 18 found increased wild-type KRAS expression in HCC compared with non-tumourous liver, which correlated with tumour size, proliferation and poor survival of patients. Based on the increasing evidence that an altered microRNA expression plays a role for HCC development and prognosis,12 19 the authors asked whether overexpression of KRAS in HCC might be caused by the loss of KRAS suppression due to downregulated microRNAs. Using bioinformatic analyses and reporter assays, Dietrich et al identified microRNA-622 as a direct regulator of KRAS and nicely elucidated the functional relevance of microRNA-622–KRAS interaction in HCC. Furthermore, they demonstrated that microRNA-622 expression was strongly downregulated and inversely correlated with KRAS expression in human HCC tissues. Thus, targeting wild-type KRAS might represent a promising therapeutic strategy to enhance treatment response in HCC. In this respect, Dietrich and colleagues showed that deltarasin, a novel small-molecule KRAS inhibitor, strongly inhibited proliferation and induced apoptosis in HCC cells, which was associated with the inhibition of the downstream RAF/MAPK and PI3K/AKT pathway as well as with downregulation of antiapoptotic (BCL-2 and BCL-XL) and upregulation of proapoptotic (BAX and PUMA) molecules. The antitumour effects of deltarasin were validated and confirmed in vivo in an orthotopic HCC mouse model. In a further part of their study, Dietrich et al raised the question whether the combination of sorafenib with deltarasin might increase antitumour efficacy. Indeed, KRAS inhibition by deltarasin markedly enhanced sorafenib-induced tumour cell apoptosis and inhibition of proliferation in HCC cells. Interestingly, sorafenib treatment caused a dose-dependent upregulation of KRAS in HCC cells, which was associated with the development of sorafenib resistance, and KRAS inhibition could resensitise those cells for sorafenib-induced toxicity. In accordance with enhanced sorafenib-induced and basal KRAS expression, microRNA-622 levels tended to be further downregulated in sorafenib-resistant compared with sorafenib-sensitive HCC cells. Whether downregulation of microRNA-622 is the cause or the consequence of HCC development or sorafenib resistance, respectively, remains to be elucidated.
This study addresses an emerging issue in cancer biology by unravelling the functions of a ‘wild-type oncogene’, since non-mutated RAS proteins have not been recognised as potential therapeutic targets for a long time. Also other wild-type isoforms of MAPK pathway-associated players are just beginning to be recognised as potent therapeutic targets.20 It is now known that elevation of wild-type RAF expression or enhanced RAS activity could lead to drug resistance in mutant BRAF tumours.21 Moreover, it is of high importance that mutant RAS proteins seem to cofunction with wild-type RAS isoforms.22 23
Mimics of microRNAs are an elegant tool to evaluate their functional role and might represent a promising treatment approach to restore downregulated microRNAs in patients with cancer. In fact, an antitumour efficacy of various microRNA mimics could be demonstrated in preclinical HCC models.12 First results from a phase 1 study, evaluating a liposome-formulated mimic of the tumour suppressor microRNA-34a in patients with advanced solid tumours refractory to standard therapy including HCC, showed an acceptable safety profile and evidence of antitumour activity.24 Targeting of mutant and wild-type RAS by microRNAs could also represent a potential therapeutic concept in cancer.25
Further studies are required to evaluate whether the analysis of KRAS and/or microRNA-622 expression might represent a reliable diagnostic tool to predict sorafenib response and whether the combination of sorafenib with microRNA-622 mimics or KRAS inhibitors might enhance treatment efficacy in HCC. Novel KRAS-inhibiting drugs alone or in combination with sorafenib in second-line/third-line treatment of HCC could address a currently unmet medical need.
Contributors Both authors developed the idea and drafted and wrote the manuscript.
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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