YAP1 Mediates Resistance to MEK1/2 Inhibition in Neuroblastomas with Hyperactivated RAS Signaling.

Relapsed neuroblastomas are enriched with activating mutations of the RAS-MAPK signaling pathway. The MEK1/2 inhibitor trametinib delays tumor growth but does not sustain regression in neuroblastoma preclinical models. Recent studies have implicated the Hippo pathway transcriptional coactivator protein YAP1 as an additional driver of relapsed neuroblastomas, as well as a mediator of trametinib resistance in other cancers. Here, we used a highly annotated set of high-risk neuroblastoma cellular models to modulate YAP1 expression and RAS pathway activation to test whether increased YAP1 transcriptional activity is a mechanism of MEK1/2 inhibition resistance in RAS-driven neuroblastomas. In NLF (biallelic NF1 inactivation) and SK-N-AS (NRAS Q61K) cell lines, trametinib caused a near-complete translocation of YAP1 protein into the nucleus. YAP1 depletion sensitized neuroblastoma cells to trametinib, while overexpression of constitutively active YAP1 protein induced trametinib resistance. Mechanistically, significant enhancement of G1-S cell-cycle arrest, mediated by depletion of MYC/MYCN and E2F transcriptional output, sensitized RAS-driven neuroblastomas to trametinib following YAP1 deletion. These findings underscore the importance of YAP activity in response to trametinib in RAS-driven neuroblastomas, as well as the potential for targeting YAP in a trametinib combination. SIGNIFICANCE: High-risk neuroblastomas with hyperactivated RAS signaling escape the selective pressure of MEK inhibition via YAP1-mediated transcriptional reprogramming and may be sensitive to combination therapies targeting both YAP1 and MEK.

Low-Loss Optical Waveguides for the Near Ultra-Violet and Visible Spectral Regions with Al(2)O(3) Thin Films from Atomic Layer Deposition.

In this work, we report low-loss single-mode integrated optical waveguides in the near ultra-violet and visible spectral regions with aluminum oxide (Al(2)O(3)) films using an atomic layer deposition (ALD) process. Alumina films were deposited on glass and fused silica substrates by the ALD process at substrate/chamber temperatures of 200 °C and 300 °C. Transmission spectra and waveguide measurements were performed in our alumina films with thicknesses in the range of 210 - 380 nm for the optical characterization. Those measurements allowed us to determine the optical constants (n(w) and k(w)), propagation loss, and thickness of the alumina films. The experimental results from the applied techniques show good agreement and demonstrate a low-loss optical waveguide. Our alumina thin-film waveguides is well transparent in the whole visible spectral region and also in an important region of the UV; the measured propagation loss is below 4 dB/cm down to a wavelength as short as 250 nm. The low propagation loss of these alumina guiding films, in particular in the near ultra-violet region which lacks materials with high optical performance, is extremely useful for several integrated optic applications.