Advances in Targeting the Ras/Raf/MEK/Erk Mitogen-Activated Protein Kinase Cascade with MEK Inhibitors for Cancer Therapy

Friday, Bret B.; Adjei, Alex A.

doi:10.1158/1078-0432.ccr-07-4790

Cited by 341 publications

(238 citation statements)

References 37 publications

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“…S7) and 0.1 M (Fig. S2 and Table S1) (30). Due to its high potency and selectivity, the MEK inhibitor PD0325901 was used to interrogate the MAPK pathway.…”

Section: Resultsmentioning

confidence: 99%

Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer

Sos

Fischer

Ullrich

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

240

235

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In cancer, genetically activated proto-oncogenes often induce ''upstream'' dependency on the activity of the mutant oncoprotein. Therapeutic inhibition of these activated oncoproteins can induce massive apoptosis of tumor cells, leading to sometimes dramatic tumor regressions in patients. The PI3K and MAPK signaling pathways are central regulators of oncogenic transformation and tumor maintenance. We hypothesized that upstream dependency engages either one of these pathways preferentially to induce ''downstream'' dependency. Therefore, we analyzed whether downstream pathway dependency segregates by genetic aberrations upstream in lung cancer cell lines. Here, we show by systematically linking drug response to genomic aberrations in non-small-cell lung cancer, as well as in cell lines of other tumor types and in a series of in vivo cancer models, that tumors with genetically activated receptor tyrosine kinases depend on PI3K signaling, whereas tumors with mutations in the RAS/RAF axis depend on MAPK signaling. However, efficacy of downstream pathway inhibition was limited by release of negative feedback loops on the reciprocal pathway. By contrast, combined blockade of both pathways was able to overcome the reciprocal pathway activation induced by inhibitor-mediated release of negative feedback loops and resulted in a significant increase in apoptosis and tumor shrinkage. Thus, by using a systematic chemo-genomics approach, we identify genetic lesions connected to PI3K and MAPK pathway activation and provide a rationale for combined inhibition of both pathways. Our findings may have implications for patient stratification in clinical trials.cancer genomics ͉ combination therapy ͉ high-throughput cell line screening ͉ oncogene dependency

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“…S7) and 0.1 M (Fig. S2 and Table S1) (30). Due to its high potency and selectivity, the MEK inhibitor PD0325901 was used to interrogate the MAPK pathway.…”

Section: Resultsmentioning

confidence: 99%

Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer

Sos

Fischer

Ullrich

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

240

235

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“…Among these, the Ras/mitogen-activated protein kinase kinase (MEK)/ERK signaling pathway has been established (23). Novel treatments targeting the RSK, PI3K/Akt and MEK/ERK signaling pathways are currently under evaluation in numerous types of tumors in clinical trials (24)(25)(26).…”

Section: A B Discussionmentioning

confidence: 99%

Luteolin, a novel p90 ribosomal S6 kinase inhibitor, suppresses proliferation and migration in leukemia cells

Deng

Jiang

et al. 2017

Oncology Letters

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Abstract. Ribosomal S6 kinases (RSKs) are directly regulated by extracellular signal-regulated kinase (ERK) signaling and are implicated in cell growth, survival, motility and senescence. The present study observed that RSK1 was overexpressed in primary untreated leukemia patient bone marrow samples compared with the expression at the complete remission stage, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, a high RSK1 expression (relative expression ≥10) was associated with a significantly shorter overall survival (P=0.038) compared with that in patients with low RSK1 expression (relative expression <10). The current study also investigated the effect of luteolin, a novel p90 ribosomal S6 kinase (RSK) inhibitor extracted from Reseda odorata L., which shows strong biochemical functions including anti-allergy, anti-inflammation and anti-cancer functions, in MOLM-13 and Kasumi-1 leukemic cells. The cell viability, apoptosis and migration ability analysis were assessed by performing a cell counting kit-8 assay, Annexin V-FITC/PI double staining and migration filter assay, respectively. The results indicated that luteolin inhibited the growth of the leukemic cell lines through induction of apoptosis, while the migration ability was also suppressed. Overexpression of RSK1 by plasmid transfection was found to decrease the luteolin-induced apoptosis and migration capabilities. By contrast, knockdown of the RSK1 expression by small interfering RNA appeared to induce the same effect as luteolin on MOLM-13 and Kasumi-1 leukemic cells. In conclusion, these results suggest that luteolin inhibits leukemic cell proliferation and induces apoptosis by inhibition of the RSK1 pathways. IntroductionRibosomal S6 kinases (RSKs) are a family of serine/threonine protein kinases that are directly regulated by extracellular signal-regulated kinase (ERK) signaling. RSK1, a member of the RSK family, was initially identified as an X-linked gene in patients with mental retardation (1-3). Typically, RSK is expressed in the cerebellum during embryogenesis and silenced postnatally. Aberrant RSK signaling is integral for various types of cancer, including breast, colon and renal cancer, as well as melanoma. Li et al (4) observed that the p90 RSK2-cAMP response element-binding protein (CREB) pathway is commonly activated in diverse metastatic human cancer cells. Degen et al (5) also demonstrated this phenomenon, and further observed that overexpression of RSK3 and RSK1 supports cellular proliferation under the PI3K signaling pathway blockade. This occurs through the inhibition of apoptosis and regulation of cellular translation in squamous carcinoma cell through phosphorylation of RSK and eukaryotic translation initiation factor 4B. It is thus reported that RSK1 serves a role in squamous carcinoma cell growth and proliferation. In addition, Cohen et al (6) observed that RSK1 overexpression is associated with sunitinib resistance in renal cell carcinoma cell lines. Elf et al (7) also reported that, altho...

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“…The key signaling networks that promote and sustain cancer (e.g., RAS/RAF/MEK/ERK and PI3K/Akt/mTOR pathways) hold significant targets for combination treatments, and a plethora of inhibitors have been developed for enzymes within these pathways [80]. Monotherapies often fail over time due to the prevailing mutations common to components in the key signaling pathways and their interchangeable nature [81], making combination therapy nearly a necessity.…”

Section: Simultaneously Targeting Major Oncogenic Pathways By Multiplmentioning

confidence: 99%

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

Kemp

Shim

Heo

et al. 2016

Advanced Drug Delivery Reviews

416

258

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a b s t r a c t a r t i c l e i n f oThe dynamic and versatile nature of diseases such as cancer has been a pivotal challenge for developing efficient and safe therapies. Cancer treatments using a single therapeutic agent often result in limited clinical outcomes due to tumor heterogeneity and drug resistance. Combination therapies using multiple therapeutic modalities can synergistically elevate anti-cancer activity while lowering doses of each agent, hence, reducing side effects. Co-administration of multiple therapeutic agents requires a delivery platform that can normalize pharmacokinetics and pharmacodynamics of the agents, prolong circulation, selectively accumulate, specifically bind to the target, and enable controlled release in target site. Nanomaterials, such as polymeric nanoparticles, gold nanoparticles/cages/shells, and carbon nanomaterials, have the desired properties, and they can mediate therapeutic effects different from those generated by small molecule drugs (e.g., gene therapy, photothermal therapy, photodynamic therapy, and radiotherapy). This review aims to provide an overview of developing multi-modal therapies using nanomaterials ("combo" nanomedicine) along with the rationale, up-to-date progress, further considerations, and the crucial roles of interdisciplinary approaches.

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Advances in Targeting the Ras/Raf/MEK/Erk Mitogen-Activated Protein Kinase Cascade with MEK Inhibitors for Cancer Therapy

Cited by 341 publications

References 37 publications

Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer

Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer

Luteolin, a novel p90 ribosomal S6 kinase inhibitor, suppresses proliferation and migration in leukemia cells

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

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