Targeting cancer with kinase inhibitors

Größ, Stefan; Rahal, Rami; Stransky, Nicolas; Lengauer, Christoph; Hoeflich, Klaus P.

doi:10.1172/jci76094

Cited by 387 publications

(304 citation statements)

References 146 publications

(144 reference statements)

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“…Cancer development and progression involve coordinate changes in both oncogene and tumor suppressor function (1,2). Specific protein phosphatases, such as protein phosphatase 2A (PP2A), act as critical negative regulators of oncogenic signaling and are modulated by physiological and pathological mechanisms (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth

Sangodkar¹,

Perl²,

Tohmé³

et al. 2017

Journal of Clinical Investigation

163

230

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Section: Introductionmentioning

confidence: 99%

Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth

Sangodkar¹,

Perl²,

Tohmé³

et al. 2017

Journal of Clinical Investigation

163

230

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“…These novel targeted therapies are based on advances in our understanding of key cellular networks and nodal points involved in tumor development and progression [5]. Genomic studies have indeed highlighted the importance of 'driver' somatic alterations that activate crucial oncoproteins originating cancers with an addictive dependency.…”

Section: Introductionmentioning

confidence: 99%

On the pharmacogenetics of non-small cell lung cancer treatment

Santarpía

Rolfo

Peters

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction. Despite many clinical efforts, non-small-cell lung cancer (NSCLC) has a dismal 5-year survival rate of 16%, and high incidence of recurrence. The success of biologically targeted agents, as well as the activity of well-established chemotherapeutic regimens, has been limited by inherited/ acquired resistance, and biomarkers to adapt the prescription of anticancer drugs to patients' features are urgently warranted. Areas covered. In oncology, pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best match the individual and tumor genetic profile, thus allowing maximum activity and minimal toxicity. The present review summarizes the main findings on NSCLC pharmacogenetics, critically reappraising the most important studies on polymorphisms correlated with outcome of pemetrexed and EGFR-inhibitors, and provides perspective on clinical application of genomic tests for treatment decision-making. Expert Opinion. A major challenge in NSCLC is the identification of subgroups of diseases/patients that will truly benefit from specific treatments. Ideally, convenient and minimally invasive tests to decipher biomarkers of chemosensitivity/resistance and toxicity should be developed alongside novel anticancer treatments. Integration with the latest generation of whole-genome analyses and liquid biopsies as well as prospective validation in large cohorts of patients will overcome the limitations of the traditional pharmacogenetic approaches. ARTICLE HISTORY

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“…For example, as has recently been reported for mouse muscle, stimulation of protein kinase A results in increased proteasome‐mediated protein degradation, whereas treatment with protein phosphatase 1 decreases proteasome‐mediated protein degradation 50. Thus, with further work, it is highly probable that protein kinase and phosphatase inhibitors can be used to modulate protein degradation levels in either direction, work that will no doubt be accelerated by the cancer field's push to identify effective protein kinase and phosphatase inhibitors that are safe for human use 51, 52. Inhibition/activation of kinases and phosphatases may also prove useful in other respects.…”

Section: Discussionmentioning

confidence: 99%

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

Lehmann

Bass

Barratt

et al. 2017

J cachexia sarcopenia muscle

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BackgroundSkeletal muscle is central to locomotion and metabolic homeostasis. The laboratory worm Caenorhabditis elegans has been developed into a genomic model for assessing the genes and signals that regulate muscle development and protein degradation. Past work has identified a receptor tyrosine kinase signalling network that combinatorially controls autophagy, nerve signal to muscle to oppose proteasome‐based degradation, and extracellular matrix‐based signals that control calpain and caspase activation. The last two discoveries were enabled by following up results from a functional genomic screen of known regulators of muscle. Recently, a screen of the kinome requirement for muscle homeostasis identified roughly 40% of kinases as required for C. elegans muscle health; 80 have identified human orthologues and 53 are known to be expressed in skeletal muscle. To complement this kinome screen, here, we screen most of the phosphatases in C. elegans . MethodsRNA interference was used to knockdown phosphatase‐encoding genes. Knockdown was first conducted during development with positive results also knocked down only in fully developed adult muscle. Protein homeostasis, mitochondrial structure, and sarcomere structure were assessed using transgenic reporter proteins. Genes identified as being required to prevent protein degradation were also knocked down in conditions that blocked proteasome or autophagic degradation. Genes identified as being required to prevent autophagic degradation were also assessed for autophagic vesicle accumulation using another transgenic reporter. Lastly, bioinformatics were used to look for overlap between kinases and phosphatases required for muscle homeostasis, and the prediction that one phosphatase was required to prevent mitogen‐activated protein kinase activation was assessed by western blot.ResultsA little over half of all phosphatases are each required to prevent abnormal development or maintenance of muscle. Eighty‐six of these phosphatases have known human orthologues, 57 of which are known to be expressed in human skeletal muscle. Of the phosphatases required to prevent abnormal muscle protein degradation, roughly half are required to prevent increased autophagy.ConclusionsA significant portion of both the kinome and phosphatome are required for establishing and maintaining C. elegans muscle health. Autophagy appears to be the most commonly triggered form of protein degradation in response to disruption of phosphorylation‐based signalling. The results from these screens provide measurable phenotypes for analysing the combined contribution of kinases and phosphatases in a multi‐cellular organism and suggest new potential regulators of human skeletal muscle for further analysis.

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Targeting cancer with kinase inhibitors

Cited by 387 publications

References 146 publications

Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth

Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth

On the pharmacogenetics of non-small cell lung cancer treatment

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

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