Frequent Mutations in TP53 and CDKN2A Found by Next-Generation Sequencing of Head and Neck Cancer Cell Lines

Nichols, Anthony C.; Yoo, John; Palma, David A.; Fung, Kevin; Franklin, Jason; Koropatnick, James; Mymryk, Joe S.; Batada, Nizar N.; Barrett, John W.

doi:10.1001/archoto.2012.1558

Cited by 44 publications

(42 citation statements)

References 16 publications

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“…In melanoma cells, the main cytotoxicity associated with pevonedistat-induced rereplication appeared to be the induction of senescence, which correlated with the presence of functional p16 tumor suppressor protein (27). However, we failed to detect senescence in Cal27 or in FaDu cells, presumably because they both lack functional p16 protein and additionally have inactivating mutations in the p53 tumor suppressor proteins (48)(49)(50). Furthermore, pevonedistatinduced growth inhibition in Cal27 or in FaDu cells was not associated with apoptosis.…”

Section: Discussionmentioning

confidence: 62%

The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors

Vanderdys

Allak

Guessous

et al. 2018

Molecular Cancer Therapeutics

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The cullin RING E3 ubiquitin ligase 4 (CRL4) with its substrate receptor CDT2 (CRL4-CDT2) is emerging as a critical regulator of DNA replication through targeting CDT1, SET8, and p21 for ubiquitin-dependent proteolysis. The aberrant increased stability of these proteins in cells with inactivated CRL4-CDT2 results in DNA rereplication, which is deleterious to cells due to the accumulation of replication intermediates and stalled replication forks. Here, we demonstrate that CDT2 is overexpressed in head and neck squamous cell carcinoma (HNSCC), and its depletion by siRNA inhibits the proliferation of human papilloma virusnegative (HPV-ve) HNSCC cells primarily through the induction of rereplication. Treatment of HNSCC with the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924), which inhibits all cullin-based ligases, induces significant rereplication and inhibits HNSCC cell proliferation in culture and HNSCC xenografts in mice. Pevonedistat additionally sensitizes HNSCC cells to ionizing radiation (IR) and enhances IR-induced suppression of xenografts in mice. Induction of rereplication via CDT2 depletion, or via the stabilization or activation of CDT1, also radiosensitizes HNSCC cells. Collectively, these results demonstrate that induction of rereplication represents a novel approach to treating radioresistant HNSCC tumors and suggest that pevonedistat may be considered as an adjuvant for IR-based treatments.

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Section: Discussionmentioning

confidence: 62%

The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors

Vanderdys

Allak

Guessous

et al. 2018

Molecular Cancer Therapeutics

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“…While many of these mutations occur randomly, recent next-generation sequencing approaches have identified mutations in common genes or their resultant protein pathways including TP53, NOTCH, PIK3CA , and CDKN2A (10-12). In fact, it is estimated that approximately 80% of HPV-negative (HPV−) HNCs harbor mutations in TP53 resulting in impaired or absent function of its encoded protein p53 (10-12). …”

Section: Introductionmentioning

confidence: 99%

“…p107 and p130) besides Rb are targeted by E7(14-16). This coordinated perturbation of two critical tumor suppressor pathways results in uncontrolled growth and proliferation although with a mutational landscape that is significantly restricted when compared to HPV− HNC (10-12). …”

Section: Introductionmentioning

confidence: 99%

Enhanced Radiation Sensitivity in HPV-Positive Head and Neck Cancer

et al. 2013

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Patients with human papillomavirus associated (HPV+) head and neck cancer (HNC) demonstrate significantly improved survival outcome compared to those with HPV− negative (HPV−) tumors. Published data examining this difference offers conflicting results to date. We systematically investigated the radiation sensitivity of all available validated HPV+ HNC cell lines and a series of HPV− HNC cell lines using in vitro and in vivo techniques. HPV+ HNCs exhibited greater intrinsic radiation sensitivity (average SF2 HPV− 0.59 vs. HPV+ 0.22, p<0.0001), corresponding with a prolonged G2/M cell cycle arrest and increased apoptosis following radiation exposure (percent change 0% vs. 85%, p=0.002). A genome-wide microarray was used to compare gene-expression 24 hours following radiation between HPV+ and HPV− cell lines. Multiple genes in TP53 pathway were upregulated in HPV+ cells (Z score 4.90), including a 4.6 fold increase in TP53 (p<0.0001). Using immortalized human tonsillar epithelial cells, increased radiation sensitivity was seen in cell expressing HPV-16 E6 despite the effect of E6 to degrade p53. This suggested that low levels of normally functioning p53 in HPV+ HNC cells could be activated by radiation, leading to cell death. Consistent with this, more complete knockdown of TP53 by siRNA resulted in radiation resistance. These results provide clear evidence, and a supporting mechanism, for increased radiation sensitivity in HPV+ HNC relative to HPV− HNC. This issue is under active investigation in a series of clinical trials attempting to de-escalate radiation (and chemotherapy) in selected patients with HPV+ HNC in light of their favorable overall survival outcome.

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“…We have previously confirmed the identity of these HNSCC cell lines by short tandem repeat profiling [9]. All cell lines were grown in DMEM/F12 supplemented with 10% FBS (Gibco), 400 ng/ml hydrocortisone (Wisent) and penicillin (100 IU/ml) and streptomycin (100 μg/ml) (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Vaccinia Virus Outperforms a Panel of Other Poxviruses as a Potent Oncolytic Agent for the Control of Head and Neck Squamous Cell Carcinoma Cell Lines

Nichols

Yoo²,

Um³

et al. 2013

Intervirology

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Background: Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer worldwide. Existing therapies for advanced tumors have high failure rates and can have severe consequences in terms of pain, disfigurement, and poor speech and swallowing function. New treatment strategies are needed to improve outcomes for patients suffering with this disease and oncolytic viruses represent a promising approach. Methods: We infected six well-characterized HNSCC cell lines (Cal27, Detroit562, FaDu, SCC4, SCC15, SCC25), with increasing doses of a panel of poxviruses (including myxoma, vaccinia, raccoonpox and tanapox viruses) modified to express green fluorescence protein to determine which virus was the most effective oncolytic agent in cell-based assays. Results: While myxoma, raccoonpox and tanapox displayed differing efficacy in the panel of cell lines, vaccinia virus was the most potent of the tested poxviruses and was highly effective in controlling cell growth in all cell lines. Conclusion: Oncolytic poxviruses, particularly vaccinia virus, were effective in killing HNSCC in vitro and hold promise as potential treatments for patients with HNSCC.

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Frequent Mutations in TP53 and CDKN2A Found by Next-Generation Sequencing of Head and Neck Cancer Cell Lines

Abstract: High-throughput sequencing of head and neck cancer cell lines revealed similar mutations to those observed in primary tumors. Thus, these lines reflect the tumor biology of HNSCC and can serve as valuable models to study HNSCC in vitro.

Cited by 44 publications

References 16 publications

The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors

The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors

Enhanced Radiation Sensitivity in HPV-Positive Head and Neck Cancer

Vaccinia Virus Outperforms a Panel of Other Poxviruses as a Potent Oncolytic Agent for the Control of Head and Neck Squamous Cell Carcinoma Cell Lines

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