October 21, 2015

Study of Integrative Radiogenomic Profiling Identifies BRAF Mutations as Novel Radiotherapeutic Targets in Lung Adenocarcinomas

MEK inhibitors can render them vulnerable to radiation

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Patients with non-small cell lung cancer (NSCLC) display a wide spectrum of oncologic outcomes, suggesting significant underlying biologic diversity. However, with few exceptions, therapeutic management is now largely homogeneous for any given stage of the cancer. Recent research suggests that this may be changing.

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The research demonstrated the successful use of cancer genomic data to identify genetic determinants of radiation resistance in the disease, opening the possibility of designing more accurate, genotype-directed radiotherapy. Research results were presented to the 2015 annual meeting of the American Society for Radiology Oncology (ASTRO) in San Antonio, Texas.

Investigators at Cleveland Clinic, the Broad Institute and Dana-Farber Cancer Institute profiled a total of 104 lung cancer cell lines in the laboratory setting, including 89 NSCLC lines and 15 small cell lung cancer (SCLC) lines. These cell lines were then exposed to radiation and analyzed for survival after radiation delivery. The investigators then assessed radiosensitivity and explored genomic correlates.

“Correlation with cancer genomic data revealed BRAF mutations were found among the most resistant adenocarcinoma (ACA) cancer cell lines,” said presenter and lead author Eui Kyu Chie, MD, PhD, a visiting scholar and postdoctoral research fellow in the Department of Translational Hematology and Oncology Research at Cleveland Clinic’s Cancer Center. “When radiation survival distributions were compared by neomorphic mutation status, BRAF-mutant cell lines were significantly more resistant than BRAF wild-type ACA lines.”

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Radiosensitivity variation greater within cell lineages

Clinical experience and the literature led investigators to expect variations in radiation survival across lineages, but in fact, radiosensitivity varied more within lineages than across them, with a sixfold difference in integral survival among ACA lines, according to the abstract describing the research.

If BRAF mutations were associated with radiation resistance in lung adenocarcinoma, did that open the window to new therapy? The investigators selected commercially available MEK inhibitors, specifically selumetinib, to be radiosensitizers in select BRAF-mutant lung ACA. These have the potential to open an avenue of genotype-directed therapy that could impact between 4 and 6 percent of patients with lung ACA, a frequency comparable to that of ALK rearrangements (4 percent) or EGFR mutations (10 percent), according to the abstract.

“It was indeed quite surprising to find a single mutation having such a huge impact on radiation response,” says Dr. Chie. “On the other hand, it was not surprising at all, as certain phenomenon was exactly what we were expecting to show from pertinent research as done in the current study.”

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Researchers may incorporate patient-derived xenografts in next phase of study

The research can now move a step closer to the clinic. Since each cancer cell line represents a unique genetic profile, it can function as a guideline, says Dr. Chie. Unfortunately, the diversity of each and every patient cannot be reflected in these cell lines. Therefore, he said, the next phase of study under discussion is to incorporate patient-derived xenografts to provide answers to the more diverse tumors oncologists face every day in the clinic.

“We have shown that tumors bearing a certain mutation, which was BRAF mutation, among lung adenocarcinoma showed far less response to radiation in comparison to other subtypes. Although radiation has been widely used as a major tool in the fight against lung cancer, strategies were mainly based on the clinical framework in the general population,” says Dr. Chie. “This study is the first of its kind to show selective radiation response. Thus, we may be able to provide more patient-centered care by selecting patients who would benefit most from radiotherapy.” Animal study is currently underway, he says.

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