Identification of genetic drivers of radiotherapy sensitivity opens door to treatment optimization

By Nick Paul Taylor, The Science Advisory Board contributing writer

October 24, 2022 -- Using in silico and experimental profiling platforms, researchers at Northwestern Medicine have identified genetic biomarkers of radiation sensitivity, pointing to opportunities to use genomics to guide radiotherapy treatment for cancer patients.

To date, radiotherapy has largely missed out on the genomic insights that have transformed other forms of cancer care. While the intervention remains a mainstay of many treatment plans, it is given without accounting for the genetic variation across tumors. The continued use of generic treatment strategies, rather than regimens tailored to tumor genomics, suggests patients are being under- and over-treated.

The Northwestern Medicine researchers have worked to understand the genetic features that regulate the sensitivity of cancers to ionizing radiation and, in doing so, provide a starting point for the optimization of radiotherapy. The scientists published their findings October 12 in the journal Clinical Cancer Research.

A previously completed large-scale profiling effort formed the starting point for the study. The researchers used an algorithm to nominate variants for experimental profiling based on the radiation sensitivity data generated in the earlier study. The nominated variants "were significantly more likely to alter radiation sensitivity" than randomly selected or commonly mutated genes, according to the authors of the study.

Having made the nominations, the collaborators introduced gene variants into an immortalized upper airway lung epithelial cell line that had minimal underlying genomic alterations. The approach enabled the study of the variants without the potentially confounding effects of cancer genomic complexity.

Studying tumors from 27 different types of cancer, the researchers profiled 488 alleles from 92 genes in the cell line and validated their results in two other cell lines. The scientists developed a computational algorithm that nominated mutations in genes that were likely to affect sensitivity to radiation and then tested these mutations by placing them in several human cells, assessing their impact using high-volume arrayed phenotypic profiling.

The analyses showed that "resistance to radiation is characterized by substantial inter- and intra-gene allelic variation." Some genes, such as KEAP1, had significant intragenic allelic variation in the level of resistance, while others, including CTNNB1, displayed both resistance and sensitivity.

Further analysis identified the upregulation of amino acid transporters as a driver of radiation sensitivity. The transporters facilitate oxidative reductive capacity and cell cycle deregulation.

Dr. Mohamed Abazeed, PhD, associate professor of radiation oncology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine radiation oncologist, called the lack of incorporation of genetic data into radiation treatment "a significant unmet clinical need" and set out the implications of the work in an October 20 statement.

"This information ultimately will allow us to better calibrate the dose of radiation for patients in the clinic. We can give higher doses to more resistant tumors based on their genetic mutations and a lower dose to the more sensitive cancers, allowing us to both improve treatment efficacy and reduce toxicity. The findings hasten a new paradigm in the field of radiation therapy," Abazeed said.

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