ERK Inhibitor LY3214996 Targets ERK Pathway–Driven Cancers: A Therapeutic Approach Toward Precision Medicine

Bhagwat, Shripad V.; McMillen, William T.; Cai, Shufen; Zhao, Bo; Whitesell, Matthew; Shen, Weihua; Kindler, Lisa; Flack, Robert S.; Wu, Wenjuan; Anderson, Bryan D.; Zhai, Yan; Yuan, Xiu‐Juan; Pogue, Meghann; Horn, Robert D. Van; Rao, Xi; McCann, Denis; Dropsey, Andrew J.; Manro, Jason R.; Walgren, Jennie; Yuen, Eunice; Rodriguez, Michael J.; Plowman, Gregory D.; Tiu, Ramon V.; Joseph, Sajan; Peng, Sheng-Bin

doi:10.1158/1535-7163.mct-19-0183

Cited by 75 publications

(55 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…LY3214996 was shown to induce G1 cell cycle arrest in some cell lines of melanoma, colorectal cancer, pancreatic cancer, and NSCLC [32]. In addition, our results revealed that combined treatment of LY3214996 and sorafenib suppressed the expression of Cyclin D1 and p-Rb then increased the proportion of cells in the G0/G1 phase to enhance the anti-proliferative effect of sorafenib on Huh7 R cells, which is consistent with previous research results [28].…”

Section: Discussionsupporting

confidence: 91%

“…Sorafenib exerted anti-tumor effect mainly by inhibiting Ras/Raf/MAPK pathway but crosstalk activated PI3K/Akt pathway during this process [31]. Despite the feedback activation of p-ERK1/2, LY3214996 still shows continuous inhibition of downstream signals of ERK signaling [32]. In this study, we found that the levels of p-Akt and p-ERK1/2 in Huh7 R cells were higher than that in Huh7 cells, while p-Akt and p-P90RSK were downregulated in a combination treatment of LY3214996 and sorafenib, which revealed that PI3K/Akt pathway was activated when sorafenib treatment and inhibited ERK1/2 could suppress Akt activation.…”

Section: Discussionmentioning

confidence: 99%

“…Since the pathway from Raf to MEK to ERK was linear, ERK1/2 itself was regarded as a target and all these changes were focused on the continuous activation of ERK, the clinical development of small molecule ERK inhibitors had aroused great interest. The treatment of LY3214996, a potent, selective, ATP competitive ERK inhibitor, inhibited the pharmacodynamic biomarker, phospho-P90RSK, in cells and tumors, and was related to the exposures and antitumor activities of LY3214996 [23].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

LY3214996 relieves acquired resistance to sorafenib in hepatocellular carcinoma cells

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Due to the reactivation of ERK signaling in sorafenib-resisitant hepatocellular carcinoma (HCC) cells, in this study, the anti-cancer effect of LY3214996 (selective ERK1/2 inhibitor) combined with sorafenib on HCC cells was evaluated. Methods: Phosphorylation of the key kinases in the Ras/Raf/MAPK and PI3K/Akt pathways were detected using Western blot. Cells proliferation, migration, cell cycle and apoptosis were evaluated in Huh7 and Huh7 R cells. Results: LY3214996 significantly reduced phosphorylation levels of the tested kinases of Ras/Raf/MAPK and PI3K/Akt pathways including p-c-Raf, p-P90RSK, p-S6K and p-eIF4EBP1 activated by sorafenib, despite increased p-ERK1/2 levels. It was found that LY3214996 enhanced the anti-proliferation, anti-migration, blocking cell cycle progression and pro-apoptotic effects of sorafenib on Huh7 R cells. Conclusions: The reactivation of ERK1/2 might be highly related to molecular mechanism of acquired drug resistance. LY3214996 combined with sorafenib enhanced anti-tumor effects in HCC. Consequently, combined treatment of LY3214996 and sorafenib provides a second-line therapy for acquired resistant in advanced HCC.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

LY3214996 relieves acquired resistance to sorafenib in hepatocellular carcinoma cells

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The mark of Wnt signaling is accumulation of active β-catenin, which transfers in nucleus and acts as transcription factor to induce transcription of target genes involved in cell division [17]. MEK/ERK, an essential signaling pathway, modulates cell proliferation, differentiation and survival [18]. Activation of MEK/ERK signaling cascade regulates gene expression related with aberrant proliferation of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: PADI4 regulates osteosarcoma proliferation primarily via Wnt/β-catenin and MEK/ERK signaling pathway

Guo

Zhang

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Peptidylarginine deiminase 4 (PADI4), an important modification enzyme of proteins, has received increased attention for its role in tumorigenesis of several human cancers. However, the effect of PADI4 on osteosarcoma remains largely unknown. Here, we evaluated the impact and mechanism of PADI4 on osteosarcoma proliferation.Methods: Impact of PADI4 on proliferation of osteosarcoma cells is detected by the method of CCK8 and colony formation assay. Expression of PADI4 as well as Wnt/β-catenin and MEK/ERK signaling markers after knocking down or ectopically expressing PADI4 or PADI4 inhibitor treatment is investigated by Western blot and RT-PCR. Then we investigated relevance of the expression level of the PADI4 in osteosarcoma samples and paired normal tissues by Western blot and RT-PCR. To further confirm whether PADI4 affects osteosarcoma tumorigenesis in vivo, we performed tumor formation experiments in nude mice.Results: Firstly, ectopically expressing PADI4 showed positive regulation on colony formation capacity of osteosarcoma cells. Secondly, PADI4 stimulated Wnt/β-catenin and MEK/ERK signaling in osteosarcoma cells. Thirdly, expression of PADI4 is higher in osteosarcoma samples compared with normal tissues. In vivo experiment also verified the positive effect of PADI4 on the growth of transplanted tumors in nude mice.Conclusions: Taken together, our results revealed PADI4 promoted proliferation of osteosarcoma via Wnt/β-catenin and MEK/ERK signaling pathway. This study may expand our understanding of osteosarcoma tumorigenesis and identify PADI4 as a potential target for diagnosis and treatment of osteosarcoma.

show abstract

“…For example, 25 years ago, we diagnosed lung cancer either as small cell lung cancer or non-small cell lung cancer. This simple classification has evolved to a much more precise diagnosis at the level of the mutated protein that is precisely involved, with consequences for optimal therapy ("targeted therapy") [3][4][5]. This development implies that clinical pharmacologists should at least know the molecular pathways possibly involved in the pathophysiology of a disease and should be able to apply the outcomes of these molecular diagnostic tests to treat the disease with optimal efficacy and safety.…”

Section: Introductionmentioning

confidence: 99%

The scientific basis of rational prescribing. A guide to precision clinical pharmacology based on the WHO 6-step method

Rongen

Marquet

Gerven³

2020

Eur J Clin Pharmacol

View full text Add to dashboard Cite

Background and methods This opinion paper expanded on the WHO “six-step approach to optimal pharmacotherapy,” by detailed exploration of the underlying pharmacological and pathophysiological principles. This exercise led to the identification of a large number of domains of research that should be addressed to make clinical pharmacology progress toward “precision clinical pharmacology,” as a prerequisite for precision medicine. Result In order to improve clinical efficacy and safety in patient groups (to guide drug development) as well as in individuals (to guide therapeutic options and optimize clinical outcome), developments in clinical pharmacology should at least tackle the following: (1) molecular diagnostic assays to guide drug design and development and allow physicians to identify the optimal targets for therapy in the individual patient in a quick and precise manner (to guide selection of the right drug for the right patient); (2) the setting up and validation of biomarkers of target engagement and modification as predictors of clinical efficacy and safety; (3) integration of physiological PK/PD models and intermediate markers of pharmacological effects with the natural evolution of the disease to predict the drug dose that most effectively improves clinical outcome in patient groups and individuals, making use of advanced modeling technologies (building on deterministic models, machine-learning, and deep learning algorithms); (4) methodology to validate human or humanized in vitro, ex vivo, and in vivo models for their ability to predict clinical outcome with investigational therapies, including nucleic acids or recombinant genes together with vectors (including viruses or nanoparticles), cell therapy, or therapeutic vaccines; (5) methodological complements to the gold-standard, large Phase 3 randomized clinical trial to provide clinically relevant and reliable data on the efficacy and safety of all treatment options at the population level (pragmatic clinical trials), as well as in small groups of patients (as low as n = 1); (6) regulatory science, so as to optimize the ethical review process, documentation, and monitoring of clinical trials, improve efficiency, and reduce costs of clinical drug development; (7) interventions to effectively improve patient compliance and to rationalize polypharmacy for the reduction of adverse effects and the enhancement of therapeutic interactions; and (8) appraisal of the ecological and societal impact of drug use to safeguard against environmental hazards (following the “One Health” concept) and to reduce drug resistance. Discussion and conclusion As can be seen, precision clinical pharmacology aims at being highly translational, which will require very large panels of complementary skills. Interdisciplinary collaborations, including non-clinical pharmacologists, will be key to achieve such an ambitious program.

show abstract

ERK Inhibitor LY3214996 Targets ERK Pathway–Driven Cancers: A Therapeutic Approach Toward Precision Medicine

Cited by 75 publications

References 43 publications

LY3214996 relieves acquired resistance to sorafenib in hepatocellular carcinoma cells

LY3214996 relieves acquired resistance to sorafenib in hepatocellular carcinoma cells

WITHDRAWN: PADI4 regulates osteosarcoma proliferation primarily via Wnt/β-catenin and MEK/ERK signaling pathway

The scientific basis of rational prescribing. A guide to precision clinical pharmacology based on the WHO 6-step method

Contact Info

Product

Resources

About