GENIPAC: A Genomic Information Portal for Head and Neck Cancer Cell Systems

Lee, Bernard Kok Bang; Gan, Chai Phei; Chang, Jit Kang; Tan, Joon Liang; Fadlullah, Muhammad Zaki Hidayatullah; Rahman, Zainal Ariff Abdul; Prime, Stephen S.; Gutkind, J. Silvio; Liew, Chee Sun; Khang, Tsung Fei; Tan, Aik Choon; Cheong, Sok Ching

doi:10.1177/0022034518759038

Cited by 6 publications

(5 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To achieve this, we compared the mutational profiles of palbociclib-sensitive and -resistant cell lines as determined by cytostatic assay in Figure 1A . We found that two out of three cell line in the resistant group carried mutations in PIK3CA (H1047L and Q546R in ORL-115 and ORL-150, respectively) 12,18 , while none of the palbociclib-sensitive cell lines had any mutations in this gene ( P < 0.001; Figure 3A ). This observation was validated with a larger data set from Genomics of Drug Sensitivity in Cancer (GDSC) comprising of 789 palbociclib-treated cancer cell lines of all available cancer types in the database.…”

Section: Resultsmentioning

confidence: 97%

“…Understanding the molecular changes that could influence therapeutic response is vital for identifying subgroups that are most likely to benefit from palbociclib treatment. We leveraged on genomic information on well-characterized cell lines 12,18,24 and showed that PIK3CA mutations are associated with the resistance of OSCC cell lines to palbociclib. Using CAL27 isogenic cell lines, we confirmed that mutations in PIK3CA indeed confer resistance to palbociclib and other clinically approved CDK4/6 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of palbociclib on oral squamous cell carcinoma and the role of PIK3CA in conferring resistance

Zainal

Lee

Wong

et al. 2019

Cancer Biology & Medicine

View full text Add to dashboard Cite

Objective Lack of effective therapies remains a problem in the treatment of oral squamous cell carcinoma (OSCC), especially in patients with advanced tumors. OSCC development is driven by multiple aberrancies within the cell cycle pathway, including amplification of cyclin D1 and loss of p16. Hence, cell cycle inhibitors of the CDK4/6-cyclin D axis are appealing targets for OSCC treatment. Here, we determined the potency of palbociclib and identified genetic features that are associated with the response of palbociclib in OSCC. Methods The effect of palbociclib was evaluated in a panel of well-characterized OSCC cell lines by cell proliferation assays and further confirmed by in vivo evaluation in xenograft models. PIK3CA -mutant isogenic cell lines were used to investigate the effect of PIK3CA mutation towards palbociclib response. Results We demonstrated that 80% of OSCC cell lines are sensitive to palbociclib at sub-micromolar concentrations. Consistently, palbociclib was effective in controlling tumor growth in mice. We identified that palbociclib-resistant cells harbored mutations in PIK3CA . Using isogenic cell lines, we showed that PIK3CA mutant cells are less responsive to palbociclib as compared to wild-type cells with concurrent upregulation of CDK2 and cyclin E1 protein levels. We further demonstrated that the combination of a PI3K/mTOR inhibitor (PF-04691502) and palbociclib completely controlled tumor growth in mice. Conclusions This study demonstrated the potency of palbociclib in OSCC models and provides a rationale for the inclusion of PIK3CA testing in the clinical evaluation of CDK4/6 inhibitors and suggests combination approaches for further clinical studies.

show abstract

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Effects of palbociclib on oral squamous cell carcinoma and the role of PIK3CA in conferring resistance

Zainal

Lee

Wong

et al. 2019

Cancer Biology & Medicine

View full text Add to dashboard Cite

show abstract

“…For metabolic alterations observed in HNSCC a variety of medium and small-scale data sets have been generated as summarised by Shin et al 104 . Furthermore, a genomic information portal for HNSCC cell systems has been set up, detailing clinical and genomic information of 44 cell lines 105 .…”

Section: The Genetic Landscape In Hnscc and Its Clinical Implicationsmentioning

confidence: 99%

Clinical update on head and neck cancer: molecular biology and ongoing challenges

et al. 2019

View full text Add to dashboard Cite

Head and neck squamous cell carcinomas (HNSCCs) are an aggressive, genetically complex and difficult to treat group of cancers. In lieu of truly effective targeted therapies, surgery and radiotherapy represent the primary treatment options for most patients. But these treatments are associated with significant morbidity and a reduction in quality of life. Resistance to both radiotherapy and the only available targeted therapy, and subsequent relapse are common. Research has therefore focussed on identifying biomarkers to stratify patients into clinically meaningful groups and to develop more effective targeted therapies. However, as we are now discovering, the poor response to therapy and aggressive nature of HNSCCs is not only affected by the complex alterations in intracellular signalling pathways but is also heavily influenced by the behaviour of the extracellular microenvironment. The HNSCC tumour landscape is an environment permissive of these tumours’ aggressive nature, fostered by the actions of the immune system, the response to tumour hypoxia and the influence of the microbiome. Solving these challenges now rests on expanding our knowledge of these areas, in parallel with a greater understanding of the molecular biology of HNSCC subtypes. This update aims to build on our earlier 2014 review by bringing up to date our understanding of the molecular biology of HNSCCs and provide insights into areas of ongoing research and perspectives for the future.

show abstract

“…Different squamous cell carcinoma cell lines exhibited cell type dependent differential expression of TFAP2A and Vimentin (VIM) genes that corroborates inter cell line heterogeneity. The available HNC data bases provide clinical and genomic information on HNC cell systems (102)(103)(104). A holistic HNdb database curates all major omics data and literature on HNC-related genes (105).…”

Section: Transcriptomics Of Hncmentioning

confidence: 99%

Current Insights and Advancements in Head and Neck Cancer: Emerging Biomarkers and Therapeutics with Cues from Single Cell and 3D Model Omics Profiling

et al. 2021

View full text Add to dashboard Cite

Head and neck cancer (HNC) is among the ten leading malignancies worldwide, with India solely contributing one-third of global oral cancer cases. The current focus of all cutting-edge strategies against this global malignancy are directed towards the heterogeneous tumor microenvironment that obstructs most treatment blueprints. Subsequent to the portrayal of established information, the review details the application of single cell technology, organoids and spheroid technology in relevance to head and neck cancer and the tumor microenvironment acknowledging the resistance pattern of the heterogeneous cell population in HNC. Bioinformatic tools are used for study of differentially expressed genes and further omics data analysis. However, these tools have several challenges and limitations when analyzing single-cell gene expression data that are discussed briefly. The review further examines the omics of HNC, through comprehensive analyses of genomics, transcriptomics, proteomics, metabolomics, and epigenomics profiles. Patterns of alterations vary between patients, thus heterogeneity and molecular alterations between patients have driven the clinical significance of molecular targeted therapies. The analyses of potential molecular targets in HNC are discussed with connotation to the alteration of key pathways in HNC followed by a comprehensive study of protein kinases as novel drug targets including its ATPase and additional binding pockets, non-catalytic domains and single residues. We herein review, the therapeutic agents targeting the potential biomarkers in light of new molecular targeted therapies. In the final analysis, this review suggests that the development of improved target-specific personalized therapies can combat HNC’s global plight.

show abstract

GENIPAC: A Genomic Information Portal for Head and Neck Cancer Cell Systems

Cited by 6 publications

References 36 publications

Effects of palbociclib on oral squamous cell carcinoma and the role of PIK3CA in conferring resistance

Effects of palbociclib on oral squamous cell carcinoma and the role of PIK3CA in conferring resistance

Clinical update on head and neck cancer: molecular biology and ongoing challenges

Current Insights and Advancements in Head and Neck Cancer: Emerging Biomarkers and Therapeutics with Cues from Single Cell and 3D Model Omics Profiling

Contact Info

Product

Resources

About