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Silencing Chemoresistance Genes in Head and Neck Cancer

Two genes that make head and neck cancer patients resistant to chemotherapy have been revealed by a team of researchers led by Queen Mary University of London, who say their finding opens the way to overturning chemoresistance in this and possibly other tumour types.

The authors of the study, published in Molecular Cancer, noted that multidrug resistance was known to cause treatment failure in "a large proportion" of head and neck squamous cell carcinoma (HNSCC) patients who require multimodal therapy involving chemotherapy in conjunction with surgery and/or radiotherapy. However, there were no specific molecular biomarkers to indicate which HNSCC patients were susceptible to developing chemoresistance.

Corresponding author, Dr Muy-Teck Teh, PhD, a senior lecturer in head and neck cancer at Queen Mary's, said: "Unfortunately, there are lots of people out there who do not respond to chemotherapy or radiation.

"Treatment that doesn't work is damaging both for the NHS and patients themselves. There can be costs associated with prolonged treatment and hospital stays, and it's naturally extremely difficult for people with cancer when their treatment doesn't have the results they are hoping for."

Very Poor 5-Year Survival Because of Resistance

The team pointed out that there were 12,422 new cases of head and neck cancer each year, 90% of them HNSCCs, and the overall 5-year survival rate in advanced cases was less than 25%. A major cause of poor survival rates was treatment failure stemming from resistance to chemotherapy and/or radiotherapy.

For their study, the scientists first used transcriptome data mining to try to identify genes that could affect tumour responsiveness to chemotherapy. Then they used pharmacological and siRNA rescue functional assays to test 28 genes from 12 strains of chemoresistant cancer cell lines against cisplatin, 5-fluorouracil, paclitaxel, and docetaxel. 

Further investigation with testing for multidrug-resistance identified 10 chemoresistance genes: TOP2A, DNMT1, INHBA, CXCL8, NEK2, FOXO6, VIM, FOXM1B, NR3C1, and BIRC5, of which four, TOP2A, DNMT1, INHBA, and NEK2, were up-regulated in an HNSCC cohort of 221 patients.

First Evidence for Chemoresistance Genes

Silencing NEK2 abrogated chemoresistance in all drug-resistant cell strains, while INHBA and TOP2A were found to confer chemoresistance in the majority of the

drug-resistant cell strains, the team said, and DNMT1 showed heterogeneous results. The study provided "the first evidence for the genes NEK2 and INHBA causing chemoresistance".

Furthermore, pan-cancer Kaplan-Meier survival analysis on 21 human cancer types revealed "significant prognostic values" for INHBA and NEK2 in at least 16 cancer types. The researchers then looked through a "chemical library" often used for drug discovery, and found two substances that could target the two genes specifically. Silencing either gene made cancer cells previously unresponsive to chemotherapy almost 30 times more sensitive to the chemotherapy drug cisplatin. 

The two substances were a fungal toxin called Sirodesmin A, and the licensed anticancer drug Carfilzomib, both targeting NEK2 and INHBA. Treatment with these substances could re-sensitise resistant HNSCC cells to cisplatin.

"This shows that there may be existing drugs that can be repurposed to target new causes of disease, which can be cheaper than having to develop and produce new ones," the researchers said. "This finding requires further investigations into the potential of repurposing licensed drugs for reversing chemoresistance in HNSCC patients."

Promising Step Towards Personalised Cancer Treatments

Dr Teh said: "These results are a promising step towards cancer patients in the future receiving personalised treatment based on their genes and tumour type that give them a better survival rate and treatment outcome." He said that the study had shown that, at least in head and neck cancers, the two particular genes they found could then be targeted to fight against chemoresistance.

The authors said that their findings "could potentially extend to other cancers with elevated levels of the genes" and "may lead to novel personalised biomarker-linked

therapeutics that can prevent and/or abrogate chemoresistance in HNSCC and other tumour types with elevated NEK2 and INHBA expression".

Asked to comment by Medscape News UK, Dr Catherine Pickworth, research impact manager at Cancer Research UK, said: "Understanding and overcoming cancer's resistance to treatment is a big challenge for doctors and their patients. This study provides an important first step in understanding what drives chemoresistance in head and neck cancer, and sheds light on potential future treatment strategies. 

"Further research is needed to fully unravel the signalling pathways in this cancer, and we look forward to seeing whether any of the proposed approaches could help people with the disease in the future."

Also commenting to Medscape News UK, Professor Mark McGurk, oral and maxillofacial surgeon at University College Hospital London and co-founder and trustee of the charity Head and Neck Cancer Foundation, said: "It looks very promising. The next phase is to see if it can be applied in clinical practice."

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