Comprehensive pharmacogenomic profiling of human papillomavirus-positive and -negative squamous cell carcinoma identifies sensitivity to aurora kinase inhibition in KMT2D mutants

Kalu, Nene N.; Mazumdar, Tuhina; Peng, Shaohua; Tong, Pan; Шен, Ли; Wang, Jing; Banerjee, Upasana; Myers, Jeffrey N.; Pickering, Curtis R.; Brunell, David; Stephan, Clifford; Johnson, Faye M.

doi:10.1016/j.canlet.2018.05.029

Cited by 29 publications

(22 citation statements)

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“…High levels of ACE2 in the small intestine may explain reports of gastrointestinal distress in COVID-19 patients 32 . ACE2 expression in aerodigestive and respiratory cancer cell lines ( Figure 1b) and both normal and tumor specimens ( Figure 1c) is consistently higher in specimens with a low EMT score, suggesting that ACE2 is primarily expressed by epithelial cells in these cancers [33][34][35][36][37][38][39][40][41][42][43] . This is confirmed by a consistent negative correlation of ACE2 and EMT score in all nine cell line and tumor data sets (Table 1).…”

Section: Expression Of Ace2 By Cancer Epithelial Cellsmentioning

confidence: 99%

Lung cancer models reveal SARS-CoV-2-induced EMT contributes to COVID-19 pathophysiology

Stewart

Gay

Ramkumar

et al. 2020

Preprint

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COVID-19 is an infectious disease caused by SARS-CoV-2, which enters host cells via the cell surface proteins ACE2 and TMPRSS2. Using normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of ACE2 and TMPRSS2. We find that ACE2 expression is restricted to a select population of highly epithelial cells and is repressed by ZEB1, in concert with ZEB1's established role in promoting epithelial to mesenchymal transition (EMT). Notably, infection of lung cancer cells with SARS-CoV-2 induces metabolic and transcriptional changes consistent with EMT, including upregulation of ZEB1 and AXL, thereby downregulating ACE2 postinfection. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state and lose ACE2 expression, along with its acute respiratory distress syndrome-protective effect, in a ZEB1-dependent manner. AXL-inhibition and ZEB1-reduction, as with bemcentinib, offers a potential strategy to reverse this effect.

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Section: Expression Of Ace2 By Cancer Epithelial Cellsmentioning

confidence: 99%

Lung cancer models reveal SARS-CoV-2-induced EMT contributes to COVID-19 pathophysiology

Stewart

Gay

Ramkumar

et al. 2020

Preprint

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“…We obtained and subjected 50 human papilloma virus (HPV)-negative and 9 HPV-positive HNSCC cell lines to whole-exome sequencing, reverse-phase protein array analysis, and gene expression profiling as described previously (14,16,17). All the cell lines were genotyped by short tandem repeat analysis, and all cell lines were mycoplasma-free at the time of testing with a Mycoplasma Detection Kit (Lonza).…”

Section: Cells and Reagentsmentioning

confidence: 99%

PDK1 Mediates NOTCH1-Mutated Head and Neck Squamous Carcinoma Vulnerability to Therapeutic PI3K/mTOR Inhibition

Sambandam

Frederick

Шен

et al. 2019

Clinical Cancer Research

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Purpose: Head and neck squamous cell carcinoma (HNSCC) is driven largely by the loss of tumor suppressor genes, including NOTCH1, but lacks a biomarker-driven targeted therapy. Although the PI3K/mTOR pathway is frequently altered in HNSCC, the disease has modest clinical response rates to PI3K/mTOR inhibitors and lacks validated biomarkers of response. We tested the hypothesis that an unbiased pharmacogenomics approach to PI3K/ mTOR pathway inhibitors would identify novel, clinically relevant molecular vulnerabilities in HNSCC with loss of tumor suppressor function.Experimental Design: We assessed the degree to which responses to PI3K/mTOR inhibitors are associated with gene mutations in 59 HNSCC cell lines. Apoptosis in drug-sensitive cell lines was confirmed in vitro and in vivo. NOTCH1 pathway components and PDK1 were manipulated with drugs, gene editing, knockdown, and overexpression.Results: PI3K/mTOR inhibition caused apoptosis and decreased colony numbers in HNSCC cell lines harboring NOTCH1 loss-of-function mutations (NOTCH1 MUT ) and reduced tumor size in subcutaneous and orthotopic xenograft models. In all cell lines, NOTCH1 MUT was strongly associated with sensitivity to six PI3K/mTOR inhibitors. NOTCH1 inhibition or knockout increased NOTCH1 WT HNSCC sensitivity to PI3K/mTOR inhibition. PDK1 levels dropped following PI3K/ mTOR inhibition in NOTCH1 MUT but not NOTCH1 WT HNSCC, and PDK1 overexpression rescued apoptosis in NOTCH1 MUT cells. PDK1 and AKT inhibitors together caused apoptosis in NOTCH1 WT HNSCC but had little effect as single agents.Conclusions: Our findings suggest that NOTCH1 MUT predicts response to PI3K/mTOR inhibitors, which may lead to the first biomarker-driven targeted therapy for HNSCC, and that targeting PDK1 sensitizes NOTCH1 WT HNSCC to PI3K/ mTOR pathway inhibitors. Figure 6. AKT inhibition and PDK1 inhibition synergistically induce apoptosis in NOTCH1 WT HNSCC lines. A, NOTCH1 WT HNSCC cell lines were treated with increasing concentrations of MK2206, GSK2334470 (GSK233), or the MK2206-GSK233 combination at a fixed 1:1 ratio for 72 hours, and cell viability was measured with the CellTiter-Glo assay. The combination index (CI) values were calculated with CalcuSyn, and the fraction affected (F a ) and CI are plotted as heatmaps for all four cell lines. B, NOTCH1 WT (black text) and NOTCH1 MUT (red text) HNSCC cells were treated with 50 nmol/L GSK2126458 (GSK212), 10 mmol/L GSK233, 10 mmol/L MK2206, or the GSK233-MK2206 combination for 48 hours. Western blot analysis showed that the combination increased cleaved PARP (Cl-PARP) and cleaved caspase 3 (Cl-Casp3) in the NOTCH1 WT lines. C, Four NOTCH1 WT HNSCC cell lines were treated with 50 nmol/L GSK212, 10 mmol/L GSK233, 10 mmol/L MK2206, or the GSK233-MK2206 combination for 48 hours. Apoptosis was measured by Annexin V/propidium iodide assay, and the percentages of apoptotic cells are expressed as the mean AE SDs of three independent experiments. Ã , P < 0.001; ÃÃ , P < 0.05, two-way analysis of variance corrected for multiple com...

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“…For clonogenic assays, cells were treated for 24 h with dimethyl sulfoxide, volasertib, tepotinib, or the combination of volasertib and tepotinib and then incubated in drug‐free medium for 14–21 days. At the end of the assay, cells were washed, fixed, and stained with crystal violet as described previously (Kalu et al , ). The total number of colonies per well was estimated using the ImageJ software program (National Institutes of Health, Bethesda, MD).…”

Section: Methodsmentioning

confidence: 99%

Non‐canonical cM et regulation by vimentin mediates Plk1 inhibitor–induced apoptosis

et al. 2019

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To address the need for improved systemic therapy for non–small‐cell lung cancer ( NSCLC ), we previously demonstrated that mesenchymal NSCLC was sensitive to polo‐like kinase (Plk1) inhibitors, but the mechanisms of resistance in epithelial NSCLC remain unknown. Here, we show that cM et was differentially regulated in isogenic pairs of epithelial and mesenchymal cell lines. Plk1 inhibition inhibits cM et phosphorylation only in mesenchymal cells. Constitutively active cM et abrogates Plk1 inhibitor–induced apoptosis. Likewise, cM et silencing or inhibition enhances Plk1 inhibitor–induced apoptosis. Cells with acquired resistance to Plk1 inhibitors are more epithelial than their parental cells and maintain cM et activation after Plk1 inhibition. In four animal NSCLC models, mesenchymal tumors were more sensitive to Plk1 inhibition alone than were epithelial tumors. The combination of cM et and Plk1 inhibition led to regression of tumors that did not regrow when drug treatment was stopped. Plk1 inhibition did not affect HGF levels but did decrease vimentin phosphorylation, which regulates cM et phosphorylation via β1‐integrin. This research defines a heretofore unknown mechanism of ligand‐independent activation of cM et downstream of Plk1 and an effective combination therapy.

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Comprehensive pharmacogenomic profiling of human papillomavirus-positive and -negative squamous cell carcinoma identifies sensitivity to aurora kinase inhibition in KMT2D mutants

Cited by 29 publications

References 46 publications

Lung cancer models reveal SARS-CoV-2-induced EMT contributes to COVID-19 pathophysiology

Lung cancer models reveal SARS-CoV-2-induced EMT contributes to COVID-19 pathophysiology

PDK1 Mediates NOTCH1-Mutated Head and Neck Squamous Carcinoma Vulnerability to Therapeutic PI3K/mTOR Inhibition

Non‐canonical cM et regulation by vimentin mediates Plk1 inhibitor–induced apoptosis

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