Proteomic and genomic integration identifies kinase and differentiation determinants of kinase inhibitor sensitivity in leukemia cells

Casado, Pedro; Wilkes, Edmund H.; Miraki-Moud, Farideh; Hadi, Marym M; Río-Machín, Ana; Rajeeve, Vinothini; Pike, Rebecca; Iqbal, Saqib; Marfà, Santiago; Lea, Nicholas; Best, Steven; Gribben, John G.; Fitzgibbon, Jude; Cutillas, Pedro R.

doi:10.1038/leu.2017.349

Cited by 11 publications

(37 citation statements)

References 2 publications

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“…Continuing this trend, most approved drugs for cancer target tyrosine kinases, and more broadly, kinases are the most common targets for cancer currently in clinical trials (167). Interrogating kinase activity to better understand cancer treatment response has also been highly effective (168)(169)(170). However, despite these successes, more than half of the kinome remains untargeted, even when considering nonclinically approved small molecules.…”

Section: The Druggable Phosphoproteomementioning

confidence: 99%

Illuminating the dark phosphoproteome

et al. 2019

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Protein phosphorylation is a major regulator of protein function and biological outcomes. This was first recognized through functional biochemical experiments, and in the past decade, major technological advances in mass spectrometry have enabled the study of protein phosphorylation on a global scale. This rapidly growing field of phosphoproteomics has revealed that more than 100,000 distinct phosphorylation events occur in human cells, which likely affect the function of every protein. Phosphoproteomics has improved the understanding of the function of even the most well-characterized protein kinases by revealing new downstream substrates and biology. However, current biochemical and bioinformatic approaches have only identified kinases for less than 5% of the phosphoproteome, and functional assignments of phosphosites are almost negligible. Notably, our understanding of the relationship between kinases and their substrates follows a power law distribution, with almost 90% of phosphorylation sites currently assigned to the top 20% of kinases. In addition, more than 150 kinases do not have a single known substrate. Despite a small group of kinases dominating biomedical research, the number of substrates assigned to a kinase does not correlate with disease relevance as determined by pathogenic human mutation prevalence and mouse model phenotypes. Improving our understanding of the substrates targeted by all kinases and functionally annotating the phosphoproteome will be broadly beneficial. Advances in phosphoproteomics technologies, combined with functional screening approaches, should make it feasible to illuminate the connectivity and functionality of the entire phosphoproteome, providing enormous opportunities for discovering new biology, therapeutic targets, and possibly diagnostics.

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Section: The Druggable Phosphoproteomementioning

confidence: 99%

Illuminating the dark phosphoproteome

et al. 2019

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“…To investigate the biological relevance of the network circuitries encoded in our PDT dataset in a larger and more clinically relevant set of cancer models, we measured our markers of network topology in 36 primary acute myeloid leukemia (AML) biopsies. Phosphoproteomics and drug sensitivity data for these models have been recently published 15 . As reported before 15 , primary AML cells showed highly heterogeneous responses to treatments with inhibitors of MEK1/2, FLT3/PKC, PAK isoforms, P38 and CK2 ( Fig.…”

Section: Identification Of Network Circuitries In Cancer Cells Of Dismentioning

confidence: 99%

“…Phosphoproteomics and drug sensitivity data for these models have been recently published 15 . As reported before 15 , primary AML cells showed highly heterogeneous responses to treatments with inhibitors of MEK1/2, FLT3/PKC, PAK isoforms, P38 and CK2 ( Fig. 4a).…”

Section: Identification Of Network Circuitries In Cancer Cells Of Dismentioning

confidence: 99%

“…In addition, since they use data from different cell types and organisms, such networks consist of composite topologies that are not always representative of how signaling may be wired in a given cell population. Aside from in silico methods, experimental approaches for kinome analysis entail measuring kinase expression 8,9 , their phosphorylation 10,11 , enzymatic activity 12,13 , or a combination of these 14,15 , without revealing new information on the kinase-kinase relationships that define signaling cascades and network circuitry. Because of these limitations, comparative systematic analysis of biochemical network topologies has so far been restricted to the analysis of metabolic, protein-protein interaction and transcription factor networks 16,17 .…”

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confidence: 99%

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Reconstructing kinase network topologies from phosphoproteomics data reveals cancer-associated rewiring

et al. 2020

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“…Downloaded by guest on July 10, 2020 not be applicable to those treated with induction therapies other than 7 + 3. While the results presented here are informative and, in principle, point to the potential of personalized therapy for refractory AML, their applicability to the clinical setting must await clinical trials to establish the safety and efficacy of such approaches (20,47,(59)(60)(61)(62)(63)(64). The biological heterogeneity described here explains the limited efficacy of current therapeutic approaches to treat refractory AML and the suboptimal ability of pretreatment disease biology, clinical factors, and gene expressionbased signatures to correctly identify, on an individual patient level, the likelihood of achieving complete remission after conventional cytotoxic induction therapy.…”

Section: Medical Sciencesmentioning

confidence: 98%