Inhibition of MEK suppresses hepatocellular carcinoma growth through independent MYC and BIM regulation

Zhou, Xiqiao; Zhu, Ailin; Gu, Xing; Xie, Guiqin

doi:10.1007/s13402-019-00432-4

Cited by 15 publications

(9 citation statements)

References 43 publications

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“…These results are consistent with data obtained from the clinical trial of selumetinib monotherapy ( 17 ). However, they are not consistent with the results of Zhou et al ’s study ( 29 ). They found that trametinib could inhibit the viability and proliferation of HCC cells, and in vivo, trametinib treatment inhibited HepG2 xenograft tumour growth and attenuated tumour invasion into surrounding tissues.…”

Section: Discussioncontrasting

confidence: 99%

The MEK inhibitors enhance the efficacy of sorafenib against hepatocellular carcinoma cells through reducing p-ERK rebound

Hou¹,

Xiao²,

Zhou³

et al. 2019

Transl. Cancer Res.

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Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide and has a poor prognosis. Sorafenib, the only targeted therapeutic agent for HCC, is a multiple kinase inhibitor with targets including RAF and VEGFR-2/3 that display a very limited ability to extend the survival of patients with advanced metastatic HCC for approximately three months. MEK inhibitors including trametinib and selumetinib have shown promising efficacy in combination with sorafenib in clinical trials. However, the mechanisms about the combined effect of these drugs remain unclear. Methods Two HCC cell lines (Bel7402 and SMMC7721) were used in the experiments. The protein expression of HCC cell lines was quantified via western blotting. Cell viability was examined by cell counting kit-8 and colony formation assays. Drug interactions between sorafenib and trametinib/selumetinib were determined by the combination index (CI) value. Results In this study, we found that short-term sorafenib treatment could inhibit the downstream RAF effectors phosphorylated (p)-MEK and p-ERK in Bel7402 and SMMC7721 cells, while long-term sorafenib treatment could induce a rebound of p-MEK and p-ERK expression in these two human HCC cell lines. We then tested the effect of sorafenib combined with two different FDA-approved MEK inhibitors, trametinib and selumetinib, in the two cell lines. Western blot analysis showed that trametinib/selumetinib could abolish the ERK activation caused by long-term sorafenib treatment. Cell counting kit-8 and colony formation assays indicated that the use of sorafenib or trametinib/selumetinib alone produced a minor effect on the proliferation of these HCC cell lines, while the combination therapies induced strong growth inhibition. CI assays using CompuSyn software indicated that the combined therapies could produce a synergistic effect in these two cell lines. In addition, mechanistic studies revealed that the combination therapies could synergistically reduce the expression of proliferation-related proteins, including cyclin D1 and c-Myc. Conclusions Taken together, our study showed that the rebound of p-ERK induced by long-term sorafenib treatment might limit the benefit of sorafenib monotherapy, and the MEK inhibitors trametinib and selumetinib could enhance the efficacy of sorafenib in HCC cells.

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Section: Discussioncontrasting

confidence: 99%

The MEK inhibitors enhance the efficacy of sorafenib against hepatocellular carcinoma cells through reducing p-ERK rebound

Hou¹,

Xiao²,

Zhou³

et al. 2019

Transl. Cancer Res.

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“…Target inhibition and downmodulation of signal transduction nodes was accompanied by cell cycle arrest and cell death responses in these MM and other studies (40,41). Trametinib exposure was associated with pro-apoptotic Bim and reduced pro-survival Bcl-xl and Mcl-1 expression, similar to other reports (42,43). Sapanisertib had no effect on Bim expression but did reduce Bad phosphorylation, thereby moderating its degradation, which logically would sustain its pro-apoptotic function.…”

Section: Discussionsupporting

confidence: 87%

Efficacy, Tolerability, and Pharmacokinetics of Combined Targeted MEK and Dual mTORC1/2 Inhibition in a Preclinical Model of Mucosal Melanoma

Wei

Hoover

Peer

et al. 2020

Molecular Cancer Therapeutics

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Melanomas arising in the mucous membranes are a rare and aggressive subtype. New treatment approaches are needed, yet accumulating sufficient evidence to improve patient outcomes is difficult. Clinical and pathological correlates between human and canine mucosal melanomas (MM) are substantial, and the relatively greater incidence of spontaneous naturally occurring MM in dogs represents a promising opportunity for predictive modeling. The genomic landscapes of human and canine MM appear highly diverse and generally lack recurring hotspot mutations associated with cutaneous melanomas. Although much remains to be determined, evidence indicates that Ras/MAPK and/or PI3K/Akt/mTOR signaling pathway activations are common in both species and may represent targets for therapeutic intervention. Sapanisertib, an mTORC1/2 inhibitor, was selected from a PI3K/mTOR inhibitor library to collaborate with MEK inhibition; the latter preclinical efficacy was demonstrated previously for canine MM. Combined inhibition of MEK and mTORC1/2, using trametinib and sapanisertib, produced apoptosis and cell cycle alteration, synergistically reducing cell survival in canine MM cell lines with varying basal signaling activation levels. Compared to individual inhibitors, a staggered sapanisertib dose, coupled with daily trametinib, was optimal for limiting primary MM xenograft growth in mice, and tumor dissemination in a metastasis model, while minimizing hematologic and renal side effects. Inhibitors downmodulated respective signaling targets and the combination additionally suppressed pathway reciprocal crosstalk. The combination did not significantly change plasma sapanisertib pharmacokinetics, however trametinib area under the curve was increased in the presence of sapanisertib. Targeting Ras/MAPK and PI3K/Akt/mTOR signal transduction pathways appear rational therapies for canine and human MM.

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“…Therefore, MAPK pathways may play a central role in liver carcinogenesis. This conclusion has been confirmed in preclinical trials, where specific MEK inhibitors blocked tumour angiogenesis and induced apoptosis by inhibiting this pathway [ 27 ]. Targeted drugs for precise molecules in this pathway have also shown promising antitumour activity in clinical trials [ 28 , 29 ].…”

Section: Introductionmentioning

confidence: 78%

“…This conclusion has been confirmed in preclinical trials, where specific MEK inhibitors blocked tumour angiogenesis Fig. 1 Signaling pathways and therapeutic targets in focus for HCC and induced apoptosis by inhibiting this pathway [27]. Targeted drugs for precise molecules in this pathway have also shown promising antitumour activity in clinical trials [28,29].…”

Section: Ras-raf-mapk Pathwaymentioning

confidence: 85%

Emerging treatment modalities for systemic therapy in hepatocellular carcinoma

Qing

Zong

et al. 2021

Biomark Res

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Hepatocellular carcinoma (HCC) has long been a major global clinical problem as one of the most common malignant tumours with a high rate of recurrence and mortality. Although potentially curative therapies are available for the early and intermediate stages, the treatment of patients with advanced HCC remains to be resolved. Fortunately, the past few years have shown the emergence of successful systemic therapies to treat HCC. At the molecular level, HCC is a heterogeneous disease, and current research on the molecular characteristics of HCC has revealed numerous therapeutic targets. Targeted agents based on signalling molecules have been successfully supported in clinical trials, and molecular targeted therapy has already become a milestone for disease management in patients with HCC. Immunotherapy, a viable approach for the treatment of HCC, recognizes the antigens expressed by the tumour and treats the tumour using the immune system of the host, making it both selective and specific. In addition, the pipeline for HCC is evolving towards combination therapies with promising clinical outcomes. More drugs designed to focus on specific pathways and immune checkpoints are being developed in the clinic. It has been demonstrated that some drugs can improve the prognosis of patients with HCC in first- or second-line settings, and these drugs have been approved by the Food and Drug Administration or are nearing approval. This review describes targeting pathways and systemic treatment strategies in HCC and summarizes effective targeted and immune-based drugs for patients with HCC and the problems encountered.

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Inhibition of MEK suppresses hepatocellular carcinoma growth through independent MYC and BIM regulation

Cited by 15 publications

References 43 publications

The MEK inhibitors enhance the efficacy of sorafenib against hepatocellular carcinoma cells through reducing p-ERK rebound

The MEK inhibitors enhance the efficacy of sorafenib against hepatocellular carcinoma cells through reducing p-ERK rebound

Efficacy, Tolerability, and Pharmacokinetics of Combined Targeted MEK and Dual mTORC1/2 Inhibition in a Preclinical Model of Mucosal Melanoma

Emerging treatment modalities for systemic therapy in hepatocellular carcinoma

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