Integrating phosphoproteomics into kinase-targeted cancer therapies in precision medicine

Wu, Xiaomo; Xing, Xiaohua; Dowlut, Djameel; Zeng, Yongyi; Liu, Jingfeng; Liu, Xiaolong

doi:10.1016/j.jprot.2018.03.033

Cited by 33 publications

(30 citation statements)

References 162 publications

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“…Regarding the field of mTOR inhibitors, our knowledge is virtually non-existent, as potential biomarkers that were identified in preclinical studies unfortunately have not been subsequently validated in clinical trials [ 173 ]. Techniques such as kinase activity profiling [ 174 , 175 ], computational analysis [ 176 ], and next-generation sequencing [ 177 ] should provide a deeper insight into active signal transduction networks and point out critical signaling hubs, new potential druggable targets, as well as drug-sensitive and drug-resistant T-ALL patients. However, it is likely that an integrated approach comprising drug sensitivity, proteomic, phosphoproteomic, and genotypic analyses of primary leukemic cells could be the key for identifying the determinants of sensitivity to targeted compounds [ 178 ].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update

Evangelisti

Chiarini

McCubrey

et al. 2018

IJMS

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood malignancy that arises from the clonal expansion of transformed T-cell precursors. Although T-ALL prognosis has significantly improved due to the development of intensive chemotherapeutic protocols, primary drug-resistant and relapsed patients still display a dismal outcome. In addition, lifelong irreversible late effects from conventional therapy are a growing problem for leukemia survivors. Therefore, novel targeted therapies are required to improve the prognosis of high-risk patients. The mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct multiprotein complexes, which are referred to as mTOR complex 1 (mTORC1) and mTORC2. These two complexes regulate a variety of physiological cellular processes including protein, lipid, and nucleotide synthesis, as well as autophagy in response to external cues. However, mTOR activity is frequently deregulated in cancer, where it plays a key oncogenetic role driving tumor cell proliferation, survival, metabolic transformation, and metastatic potential. Promising preclinical studies using mTOR inhibitors have demonstrated efficacy in many human cancer types, including T-ALL. Here, we highlight our current knowledge of mTOR signaling and inhibitors in T-ALL, with an emphasis on emerging evidence of the superior efficacy of combinations consisting of mTOR inhibitors and either traditional or targeted therapeutics.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update

Evangelisti

Chiarini

McCubrey

et al. 2018

IJMS

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“…Although the first attempt to harness immune system for treating cancer went back to the late nineteenth century [ 2 ], the capability of the immune system to recognize and fight cancer remained highly controversial for much of the twentieth century [ 3 , 4 ]. Today, nearly 120 years of basic research in immunology, molecular biology, virology, cell biology, and structural biology have advanced our understanding of the role of the immune system in the surveillance against tumors as well as the strategies exploited by tumor cells to escape such surveillance, ultimately leading to the acceptance of immunotherapy as a promising approach to tackle this dynamic and complex interplay between cancer and immunity [ [5] , [6] , [7] , [8] ].…”

Section: Introductionmentioning

confidence: 99%

Application of PD-1 Blockade in Cancer Immunotherapy

Yang

et al. 2019

Computational and Structural Biotechnology Journal

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390

281

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The programmed cell death protein 1 (PD-1) pathway has received considerable attention due to its role in eliciting the immune checkpoint response of T cells, resulting in tumor cells capable of evading immune surveillance and being highly refractory to conventional chemotherapy. Application of anti-PD-1/PD-L1 antibodies as checkpoint inhibitors is rapidly becoming a promising therapeutic approach in treating tumors, and some of them have successfully been commercialized in the past few years. However, not all patients show complete responses and adverse events have been noted, suggesting a better understanding of PD-1 pathway mediated immunosuppression is needed to predict patient response and improve treatment efficacy. Here, we review the progresses on the studies of the mechanistic role of PD-1 pathway in the tumor immune evasion, recent clinical development and commercialization of PD-1 pathway inhibitors, the toxicities associated with PD-1 blockade observed in clinical trials as well as how to improve therapeutic efficacy and safety of cancer immunotherapy.

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“…Therapeutic strategies for protein phosphorylation diseases have mainly focused on drugs that target protein kinases, although protein phosphatases are equally attractive targets [4,5]. To date, more than two dozen small-molecule protein kinase inhibitors and six therapeutic antibodies against protein tyrosine kinases have been approved by the US Food and Drug Administration (FDA) for clinical use, mainly for targeted cancer therapies [6,7]. Along with these FDA-approved drugs, hundreds of other protein kinase inhibitors are being tested in clinical trials [6,7].…”

Section: Introductionmentioning

confidence: 99%

Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics

Ferreira

Beullens

Eynde

2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Protein phosphatase 1 (PP1) catalyzes more than half of all phosphoserine/threonine dephosphorylation reactions in mammalian cells. In vivo PP1 does not exist as a free catalytic subunit but is always associated with at least one regulatory PP1-interacting protein (PIP) to generate a large set of distinct holoenzymes. Each PP1 complex controls the dephosphorylation of only a small subset of PP1 substrates. We screened the literature for genetically engineered mouse models and identified models for all PP1 isoforms and 104 PIPs. PP1 itself and at least 49 PIPs were connected to human disease-associated phenotypes. Additionally, phenotypes related to 17 PIPs were clearly linked to altered PP1 function, while such information was lacking for 32 other PIPs. We propose structural reverse genetics, which combines structural characterization of proteins with mouse genetics, to identify new PP1-related therapeutic targets. The available mouse models confirm the pleiotropic action of PP1 in health and diseases.

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Integrating phosphoproteomics into kinase-targeted cancer therapies in precision medicine

Cited by 33 publications

References 162 publications

Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update

Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update

Application of PD-1 Blockade in Cancer Immunotherapy

Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics

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