Summary: Researchers identified two genes – NEK2 and INHBA – responsible for causing chemotherapy resistance in head and neck cancer patients. Remarkably, when these genes are silenced, previously resistant cancer cells begin responding to chemotherapy.
From a chemical library, the team pinpointed two substances (Sirodesmin A and Carfilzomib) that can target these genes, making resistant cells vastly more receptive to the chemotherapy drug cisplatin.
This groundbreaking study paves the way for more personalized cancer treatments, offering hope to patients resistant to conventional therapies.
The identified genes, NEK2 and INHBA, are the first evidence of causing chemoresistance in head and neck squamous cell carcinoma (HNSCC).
Two substances, a fungal toxin (Sirodesmin A) and another from a bacterium (Carfilzomib), can make resistant cells 30 times more sensitive to chemotherapy.
Over 90% of head and neck cancers are caused by HNSCCs, with a 5-year survival rate of less than 25%.
Source: Queen Mary University London
Scientists from Queen Mary University of London have discovered two new genes that cause head and neck cancer patients to be resistant to chemotherapy, and that silencing either gene can make cancer cells previously unresponsive to chemotherapy subsequently respond to it.
The two genes discovered actively ‘work’ in most human cancer types, meaning the findings could potentially extend to other cancers with elevated levels of the genes.
The researchers also looked through a chemical library, commonly used for drug discovery, and found two substances that could target the two genes specifically and make resistant cancer cells almost 30 times more sensitive to a common chemotherapy drug called cisplatin.
They do this by reducing the levels of the two genes and could be given alongside existing chemotherapy treatment such as cisplatin. One of these substances is a fungal toxin – Sirodesmin A – and the other – Carfilzomib – comes from a bacterium.
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 research, led by Queen Mary and published in Molecular Cancer, is the first evidence for the genes NEK2 and INHBA causing chemoresistance in head and neck squamous cell carcinoma (HNSCC) and gene silencing of either gene overturning chemoresistance to multiple drugs.
The scientists first used a method known as data mining to identify genes that may be affecting tumour responsiveness to drug therapy. They tested 28 genes on 12 strains of chemoresistant cancer cell lines, finding 4 ‘significant’ genes that were particularly responsive that they then investigated further and tested multidrug-resistance.
Dr Muy-Teck Teh, senior author of the study from Queen Mary University of London, 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.
“Unfortunately, there are lots of people out there who do not respond to chemotherapy or radiation. But our study has shown that in head and neck cancers at least it is these two particular genes that could be behind this, which can then be targeted to fight against chemoresistance.
“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.”
90% of all head and neck cancers are caused by HNSCCs, with tobacco and alcohol use being key associations. There are 12,422 new cases of head and neck cancer each year, and the overall 5-year survival rate of patients with advanced HNSCC is less than 25%. A major cause of poor survival rates of HNSCC is because of treatment failure that stems from resistance to chemotherapy and/or radiotherapy.
Unlike lung and breast cancer patients, all HNSCC patients are treated with almost the same combinations of treatment irrespective of the genetic makeup of their cancer.
About this brain cancer and genetics research news
Identification of multidrug chemoresistant genes in head and neck squamous cell carcinoma cells
Multidrug resistance renders treatment failure in a large proportion of head and neck squamous cell carcinoma (HNSCC) patients that require multimodal therapy involving chemotherapy in conjunction with surgery and/or radiotherapy. Molecular events conferring chemoresistance remain unclear.
Through transcriptome datamining, 28 genes were subjected to pharmacological and siRNA rescue functional assays on 12 strains of chemoresistant cell lines each against cisplatin, 5-fluorouracil (5FU), paclitaxel (PTX) and docetaxel (DTX).
Ten multidrug chemoresistance genes (TOP2A, DNMT1, INHBA, CXCL8, NEK2, FOXO6, VIM, FOXM1B, NR3C1 and BIRC5) were identified. Of these, four genes (TOP2A, DNMT1, INHBA and NEK2) were upregulated in an HNSCC patient cohort (n = 221). Silencing NEK2 abrogated chemoresistance in all drug-resistant cell strains. INHBA and TOP2A were found to confer chemoresistance in majority of the drug-resistant cell strains whereas DNMT1 showed heterogeneous results.
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. Drug library screens identified two compounds (Sirodesmin A and Carfilzomib) targeting both INHBA and NEK2 and re-sensitised cisplatin-resistant cells.
We have provided the first evidence for NEK2 and INHBA in conferring chemoresistance in HNSCC cells and siRNA gene silencing of either gene abrogated multidrug chemoresistance. The two existing compounds could be repurposed to counteract cisplatin chemoresistance in HNSCC.
This finding 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. Further investigation is necessary to delineate their signalling mechanisms in tumour chemoresistance.