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- W2758501703 abstract "To test the hypothesis that head and neck cancer with HRAS activating mutations can be radiosensitized by inhibition of the downstream MEK/ERK or PI3K/MTOR pathways. Mutations in HRAS, KRAS, and NRAS were analyzed using cBioPortal in a head and neck cancer cohort. The Illumina TruSeq Amplicon Cancer panel was used to screen a panel of head and neck cancer cell lines for mutations in RAS-family genes. Radiation survival was assessed by clonogenic survival assay. Immunoblots were used to confirm target activation/knockdown in overexpression and knockdown studies. A tumor control dose 50% (TCD50) assay was employed to investigate radiosensitization of a mutated-HRAS head and neck cancer cell line in a flank xenograft model in nude mice. Activating mutations in one of the three RAS genes are seen in 5-10% of head and neck cancer patients. Mutations in HRAS represent over 50% of these. Screening our panel of head and neck cancer cell lines identified a canonical activating mutation in HRAS (G12V). Consistent with known roles for activated HRASG12V, SCC22B is relatively insensitive to both cetuximab and radiation. Using both in vitro and in vivo studies, cetuximab failed to radiosensitize SCC22B. Cetuximab treatment decreased AKT, but not ERK activation. Direct inhibition of the MEK/ERK or PI3K/MTOR pathway by selumetinib or BEZ235, respectively, decreased target protein activation and resulted in significant growth inhibition compared to control (p<0.05). Treatment with either selumetinib or BEZ235 radiosensitized HRASG12V expressing cells (SER 1.3-1.8) but had no effects on cells expressing wildtype HRAS. siRNA knockdown of HRAS radiosensitized SCC22B, but not SCC1 or SCC6 cells relative to non-targeting control while overexpression of HRASG12Vresulted in less sensitivity to radiation in wildtype cell lines. In vivo assessment of the radiosensitizing effects of these compounds via a TCD50 assay (5 fractions of 0, 0.5, 2, 4, 7, and 10 Gy) is pending. More than 5% of head and neck cancers harbor activating mutations in one of the RAS family of genes. These mutations lead to resistance to cetuximab, either as a single agent, or as a radiosensitizer. Inhibition of downstream targets such as the MEK/ERK and PI3K/MTOR pathways can radiosensitize tumors harboring activating mutations in HRAS. Further investigation of the safety and efficacy of these drugs in combination with chemoradiation is warranted." @default.
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- W2758501703 date "2017-10-01" @default.
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- W2758501703 title "Radiosensitization of HRAS Mutated Head and Neck Cancer" @default.
- W2758501703 doi "https://doi.org/10.1016/j.ijrobp.2017.06.2020" @default.
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