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P. Gopal

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    MA13 - Modern Technologies and Biological Factors in Radiotherapy (ID 395)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Radiotherapy
    • Presentations: 1
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      MA13.06 - Integrative Genomic Profiling Identifies BRAF Mutations as Novel Radiotherapeutic Targets in Adenocarcinomas of the Lung (ID 6199)

      16:00 - 17:30  |  Author(s): P. Gopal

      • Abstract
      • Presentation
      • Slides

      Patients with non-small cell lung cancer (NSCLC) display a wide spectrum of oncologic outcomes, suggesting significant underlying biologic diversity. However, current radiotherapeutic management is largely homogeneous for a given stage, To advance genotype-directed radiotherapy in NSCLC, we sought to identify genetic determinants of radioresistance by leveraging cancer genomic data with a recently developed high-throughput platform for measuring radiation survival.

      We used our recently validated high-throughput proliferation assay to profile 104 lung cancer cell lines, including 89 NSCLC and 15 small cell lung cancer (SCLC) lines, for radiation survival. Survival curve analyses permitted quantitative assessment of radiosensitivity. Genomic correlates of radiosensitivity were explored by calculating the information-based similarity metric and correlating genomic parameters by accessing Oncomap data from the Cancer Cell Line Encyclopedia, the COSMIC database of the Cancer Genome Project, and The Cancer Genome Atlas.

      Radiation survival across lineages reflected clinical experience regarding differential response to fractionated radiation inasmuch as lung squamous cell carcinoma and adenocarcinoma (ACA) had similar radiosensitivity, whereas SCLC and carcinoid were, respectively, more and less radiosensitive. Importantly, radiosensitivity varied more within a lineage than across lineages, with a 6-fold difference in integral survival among ACA lines. Correlation with cancer genomic data revealed BRAF mutations within the most resistant ACA lines (P = 0.0097, FDR = 0.957). A majority of the mutations identified by our analysis have been previously annotated by The Cancer Genome Atlas lung ACA dataset and all hypermorphic mutations identified were located in the highly conserved kinase domain. The majority of mutations have been known to enhance kinase activity in melanoma in a fashion analogous to the well-known BRAF V600E mutation. In line with these findings, we showed that kinase domain mutations were hypermorphic as measured by MEK and ERK1/2 phosphorylation. We also showed that exposure of wild type BRAF cells to radiation results only in a transient activation of MEK and ERK1/2. The MEK inhibitor selumetinib selectively decreased the growth of cells with kinase domain BRAF mutations and sensitized these cells to radiation.

      BRAF mutations are associated with radiation resistance in lung ACA. Our data nominates MEK inhibitors, a drug class currently in clinical use, as a targeted therapeutic in select BRAF-mutant lung ACA. Further investigation has the potential to yield an additional genotype-directed therapy that could impact up to 4-6% of patients with lung ACA, a frequency comparable to that of ALK rearrangements (4%) or EGFR mutations (10%).

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