13 December 2021

A new study has identified a gene which, when mutated, may cause chemotherapy to fail in some lymphoma patients.

Research by Nanyang Technological University, Singapore (NTU Singapore) and Singapore General Hospital (SGH) looked at why most patients with aggressive forms of non-Hodgkin’s lymphoma do not respond to traditional therapy, and why a sub-group of patients who respond initially go on to relapse and die.

Study leaders Assistant Professor Navin Verma at NTU’s Lee Kong Chian School of Medicine (LKCMedicine) and Assistant Professor Nicholas Grigoropoulos, senior consultant from the Department of Haematology at SGH, examined the publicly available genetic database of more than 1,000 UK patients.

Working with researchers at the University of Cambridge, they also analysed 167 non-Hodgkin’s lymphoma specimens from patients in the UK.

The team used advanced gene sequencing technology to map cancer-causing gene abnormalities from samples of patients whose chemotherapy failed. They found that mutations in the gene DDX3X, which codes for a protein responsible for processing and transmitting signals for cell growth, could be responsible.

The genetic data was combined with those from previous studies. Lymphoma patients with DDX3X mutations had a significantly lower survival rate than those without such mutations, the researchers found.

They also found that DDX3X mutations cause increased STAT activity, a type of signalling mechanism that allows cancer cells to survive.

When the STAT3 inhibitor WP1066 was tested, it was found it killed lymphoma cells with a DDX3X mutation more effectively than standard chemotherapy agents.

The findings are published in Molecular Cancer.

Asst Prof Navin said: “Now that we know DDX3X mutations are what make some cancer cells difficult to kill with chemotherapy, it is possible to identify patients with such mutations through lab tests before treatment starts.

“Early identification will allow clinicians to have a better understanding of general chemotherapy outcome for this group of cancer patients and enable them to offer personalised therapy from the get-go, buying precious time that would otherwise be spent on futile chemotherapy.”

The researchers are now looking to conduct further research that could lead to the development of new cancer drugs based on their findings.

Source: Kizhakeyil A, Zaini NBM, Poh ZS, Wong BHS, Loh X, Ng AS, Low ZS, Prasannan P, Gong C, Tan MGK, Nagarajan C, Huang D, Lu PW, Lim JQ, Barrans S, Ong CK, Lim ST, Chng WJ, Follows G, Hodson DJ, Du MQ, Goh YT, Tan SH, Grigoropoulos NF, Verma NK. (2021) “DDX3X loss is an adverse prognostic marker in diffuse large B-cell lymphoma and is associated with chemoresistance in aggressive non-Hodgkin lymphoma subtypes.” Molecular Cancer, doi: 10.1186/s12943-021-01437-0

Link: https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-021-01437-0

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