Wee-1 Kinase Inhibition Overcomes Cisplatin Resistance Associated with High-Risk<i>TP53</i>Mutations in Head and Neck Cancer through Mitotic Arrest Followed by Senescence

Osman, Abdullah A.; Monroe, Marcus M.; Alves, Marcus V. Ortega; Patel, Ameeta A.; Katsonis, Panagiotis; Fitzgerald, Alison L.; Neskey, David M.; Frederick, Mitchell J.; Woo, Seung Kyoon; Caulín, Carlos; Hsu, Teng Kuei; McDonald, Thomas O.; Kimmel, Marek; Meyn, Raymond E.; Lichtarge, Olivier; Myers, Jeffrey N.

doi:10.1158/1535-7163.mct-14-0735-t

Cited by 99 publications

(132 citation statements)

References 41 publications

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“…The Evolutionary Action Eq. 2 is thus generally solvable for coding mutation of proteins and quantifies the effect of mutations over multiple scales, spanning molecular, clinical, and population genetics effects (21)(22)(23)(24). Here, for each residue identified in Fig.…”

Section: Resultsmentioning

confidence: 99%

Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor

Peterson¹,

Pack²,

Wilkins

et al. 2015

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

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The neuromodulator dopamine signals through the dopamine D2 receptor (D 2 R) to modulate central nervous system functions through diverse signal transduction pathways. D 2 R is a prominent target for drug treatments in disorders where dopamine function is aberrant, such as schizophrenia. D 2 R signals through distinct G-protein and β-arrestin pathways, and drugs that are functionally selective for these pathways could have improved therapeutic potential. How D 2 R signals through the two pathways is still not well defined, and efforts to elucidate these pathways have been hampered by the lack of adequate tools for assessing the contribution of each pathway independently. To address this, Evolutionary Trace was used to produce D 2 R mutants with strongly biased signal transduction for either the G-protein or β-arrestin interactions. These mutants were used to resolve the role of G proteins and β-arrestins in D 2 R signaling assays. The results show that D 2 R interactions with the two downstream effectors are dissociable and that G-protein signaling accounts for D 2 R canonical MAP kinase signaling cascade activation, whereas β-arrestin only activates elements of this cascade under certain conditions. Nevertheless, when expressed in mice in GABAergic medium spiny neurons of the striatum, the β-arrestin-biased D 2 R caused a significant potentiation of amphetamine-induced locomotion, whereas the G proteinbiased D 2 R had minimal effects. The mutant receptors generated here provide a molecular tool set that should enable a better definition of the individual roles of G-protein and β-arrestin signaling pathways in D 2 R pharmacology, neurobiology, and associated pathologies.

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Section: Resultsmentioning

confidence: 99%

Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor

Peterson¹,

Pack²,

Wilkins

et al. 2015

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

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“…This innate ability of cancer cells to escape senescence has great significance for cancer recurrence and drug resistance [16]. There have been an increasing number of reports indicating that initiating a senescence program in solid tumors could be a potential therapeutic strategy to overcome drug resistance [17,18]. A publication by Osman et al, has shown that senescence, rather than apoptosis, is the major mechanism of cisplatin-induced response in wild-type TP53 head and neck cancer cells, and that cisplatin resistance in TP53 null or high-risk mutant TP53 cells is due to a lack of senescence [17].…”

Section: Discussionmentioning

confidence: 99%

“…There have been an increasing number of reports indicating that initiating a senescence program in solid tumors could be a potential therapeutic strategy to overcome drug resistance [17,18]. A publication by Osman et al, has shown that senescence, rather than apoptosis, is the major mechanism of cisplatin-induced response in wild-type TP53 head and neck cancer cells, and that cisplatin resistance in TP53 null or high-risk mutant TP53 cells is due to a lack of senescence [17]. Further study by this group showed that Wee-1 kinase inhibition overcame the cisplatin resistance associated with high-risk TP53 mutations in head and neck cancers through mitotic arrest followed by senescence [18].…”

Section: Discussionmentioning

confidence: 99%

Membrane-Bound CD40L Promotes Senescence and Initiates Senescence-Associated Secretory Phenotype via NF-κB Activation in Lung Adenocarcinoma

Yuan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cellular senescence acts as a barrier against tumorigenesis. The CD40L transgene, expressed in some tumor cells, not only becomes visible to antigen-presenting cells but also actively catalyzes its own termination. Here, we evaluated the effect of a membrane-bound mutant form of human CD40L (CD40L-M) on senescence and the senescence-associated secretory phenotype (SASP) in non-small cell lung cancer (NSCLC). Methods: CD40 expression levels in the NSCLC cell lines A549/TR, A549/DDP and H460 were examined by flow cytometry. Senescent cells and tissues were identified via SA-β-gal activity. Cell proliferation was visualized by EdU labeling. qRT-PCR, Western blotting, and immunofluorescence staining were conducted to assess mRNA and protein expression levels of CD40L, γ-H2A.X, p65, p-p65, IκBα, p53, p21 and p16. Cytokines secreted from transfected cells were tested by ELISA and cell migration assay. Capsid tyrosine-modified rAAV5-CD40L-M was packaged and carried out in vivo. Results: Overexpression of CD40L-M promoted senescence, inhibited proliferation, increased DNA damage-associated γ-H2A.X, and initiated the SASP in CD40-positive NSCLC cells. NF-κB signaling was activated by CD40L-M overexpression in these cells. Knockdown of NF-κB partially overcame senescence and failed to induce SASP. Furthermore, increased p53 and p21 protein levels induced by CD40L-M were also reduced following NF-κB suppression. Conclusions: These data showed that the membrane-bound CD40L mutant may promote cellular senescence and initiate the SASP of NSCLC cells in an NF-κB-dependent manner. Therefore, CD40L-M-induced senescence may be a potential approach to protect against lung adenocarcinoma.

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“…11 Preclinical studies have shown that Wee1 inhibition can sensitize cells to mitotic catastrophe following exposure to DNA damaging agents, and several studies are ongoing to test this possibility this in the clinic. 7,[12][13][14][15] Wee1 has an additional role as a Cdk2 kinase, which is relevant to the development of cancer treatment strategies that incorporate Wee1 inhibitors. 16,17 The activation of Cdk2 promotes origin firing during S-phase, and regulates the overall timing of DNA replication.…”

Section: Introductionmentioning

confidence: 99%

Cytokinetic effects of Wee1 disruption in pancreatic cancer

et al. 2016

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The Wee1 kinase, which is activated in response to DNA damage, regulates exit from G2 through inhibitory phosphorylation of Cdk1/Cdc2, and is an attractive drug target. However, recent work has highlighted effects of Cdk2 phosphorylation by Wee1 on movement through S-phase, suggesting the potential to sensitize to S-phase specific agents by Wee1 inhibitors. In this paper we applied multiparametric flow cytometry to patient-derived pancreatic cancer xenograft tumor cells to study the cell cycle perturbations of Wee1 disruption via the small molecule inhibitor MK-1775, and genetic knockdown. We find that in vitro treatment with MK-1775, and to a lesser degree, Wee1 RNA transcript knockdown, results in the striking appearance of S-phase cells prematurely entering into mitosis. This effect was not seen in vivo in any of the models tested. Here, although we noted an increase of S-phase cells expressing the damage response marker gH2AX, treatment with MK-1775 did not significantly sensitize cells to the cytidine analog gemcitabine. Treatment with MK-1775 did result in a transient but large increase in cells expressing the mitotic marker phosphorylated H3S10 that reached a peak 4 hours after treatment. This suggests a role for Wee1 regulating the progression of genomically unstable cancer cells through G2 in the absence of extrinsically-applied DNA damage. A single dose of 8Gy ionizing radiation resulted in the time-dependent accumulation of Cyclin A2 positive/phosphorylated H3S10 negative cells at the 4N position, which was abrogated by treatment with MK-1775. Consistent with these findings, a genomescale pooled RNA interference screen revealed that toxic doses of MK-1775 are suppressed by CDK2 or Cyclin A2 knockdown. These findings support G2 exit as the more significant effect of Wee1 inhibition in pancreatic cancers.

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Wee-1 Kinase Inhibition Overcomes Cisplatin Resistance Associated with High-RiskTP53Mutations in Head and Neck Cancer through Mitotic Arrest Followed by Senescence

Cited by 99 publications

References 41 publications

Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor

Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor

Membrane-Bound CD40L Promotes Senescence and Initiates Senescence-Associated Secretory Phenotype via NF-κB Activation in Lung Adenocarcinoma

Cytokinetic effects of Wee1 disruption in pancreatic cancer

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