Therapeutic targeting of tumor suppressor genes

Morris, Luc G.T.; Chan, Timothy A.

doi:10.1002/cncr.29140

Cited by 152 publications

(108 citation statements)

References 119 publications

(205 reference statements)

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“…Inhibiting PKM function as an anti-cancer therapy would be counterproductive while drugs that increase PKM catalytic activity may be of limited therapeutic value if tumors can thrive with low PKM expression. The loss of tumor suppressor genes, however, may be targeted through alternative approaches that require defining the consequent changes in pathway regulation (53,54). A detailed understanding of how low PK activity promotes proliferation may produce novel clinical strategies to treat tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation

et al. 2017

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Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNPs), and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of Hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting Pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which post-mitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM.

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Section: Discussionmentioning

confidence: 99%

Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation

et al. 2017

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“…Whereas targeting oncogenes with chemical inhibitors or therapeutic antibodies has proven to be effective for cancer therapy (Sawyers, 2004), it is not currently feasible to restore the function of mutated or deleted TSGs in the clinical setting (Morris and Chan, 2015). Rather than targeting a TSG directly, an emerging strategy is to identify ‘synthetic lethal’ genetic interactions between the TSG and other genes, such that simultaneous disruption of both gene functions causes rapid and selective cell death (Brody, 2005).…”

Section: Introductionmentioning

confidence: 99%

A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy

et al. 2016

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Summary An emerging therapeutic strategy for cancer is to induce selective lethality in a tumor by exploiting interactions between its driving mutations and specific drug targets. Here, we use a multi-species approach to develop a resource of synthetic-lethal interactions among genes mutated in cancer, including tumor suppressor genes (TSG) and druggable genes. First, we screen in yeast ~169,000 potential interactions amongst TSG orthologs and genes encoding drug targets across multiple genotoxic environments. Guided by the strongest signal, we evaluate thousands of TSG-drug combinations in HeLa cells, resulting in networks of conserved synthetic-lethal interactions. Analysis of these networks reveals that interaction stability across environments and shared gene function increase the likelihood of observing an interaction in human cancer cells. Using these rules we prioritize >105 human TSG-drug combinations for future follow-up. We validate interactions based on cell and/or patient survival, including topoisomerases with RAD17 and checkpoint kinases with BLM.

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“…Tumor-associated genetic alterations usually result in activation of oncogenes and inactivation of tumor suppressor genes, and many oncogenes and tumor suppressor genes have been determined and used for molecular targeted therapy of NSCLC 5–7 . Although important clinical advances have been achieved, the molecular mechanisms of NSCLC, especially the mechanism involved in tumor progression, are still unclear, and treatments for tumor metastasis and recurrence are still lacking 8 . Therefore, more studies are needed to further identify novel key genes which would contribute to understanding tumor progression and identifying a better way to control tumor metastasis and recurrence in NSCLC, although this is still at the exploratory stage 9 .…”

Section: Introductionmentioning

confidence: 99%

ANKRD22 promotes progression of non-small cell lung cancer through transcriptional up-regulation of E2F1

Yin

Dai

et al. 2017

Sci Rep

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Lung cancer is the leading cause of death among all malignancies due to rapid tumor progression and relapse; however, the underlying molecular mechanisms of tumor progression are unclear. In the present study, we identified ANKRD22 as a novel tumor-associated gene in non-small cell lung cancer (NSCLC). According to the clinical correlation analysis, ANKRD22 was highly expressed in primary cancerous tissue compared with adjacent cancerous tissue, and high expression levels of ANKRD22 were significantly correlated with relapse and short overall survival time. Knockdown and overexpression analysis revealed that ANKRD22 promoted tumor progression by increasing cell proliferation. In xenograft assays, knockdown of ANKRD22 or in vivo treatment with ANKRD22 siRNA inhibited tumor growth. Furthermore, ANKRD22 was shown to participate in the transcriptional regulation of E2F1, and ANKRD22 promoted cell proliferation by up-regulating the expression of E2F1 which enhanced cell cycle progression. Therefore, our studies indicated that ANKRD22 up-regulated the transcription of E2F1 and promoted the progression of NSCLC by enhancing cell proliferation. These findings suggest that ANKRD22 could potentially act as a novel therapeutic target for NSCLC.

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Therapeutic targeting of tumor suppressor genes

Cited by 152 publications

References 119 publications

Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation

Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation

A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy

ANKRD22 promotes progression of non-small cell lung cancer through transcriptional up-regulation of E2F1

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