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• W3082880931 abstract "Background Oncogenic KRAS mutant non-small cell lung cancer (NSCLC) remains treatment refractory. Even with the novel KRAS-G12C inhibitors in clinical development, caution should be taken because tumors will likely develop resistance. Subgroups of KRAS mutant NSCLC, defined by co-occurring genetic alterations in STK11/LKB1 (KL) and TP53 (KP) tumor suppressor genes, have distinct biology and therapeutic vulnerabilities. The Hippo pathway effector YAP has been shown to substitute oncogenic KRAS in promoting the growth of lung adenocarcinomas and confer resistance to MAPK pathway inhibitors and immunotherapy. Here we have examined the role of YAP in KL, KP and K-only (intact STK11/LKB1 and TP53) NSCLC cells. Methods All the cell lines were obtained from ATCC. Cell viability was assessed by CellTiter-Glo Luminescent Assay (Promega) and protein levels by western blot. YAP silencing was achieved by siRNA transfection (20 nM) using Lipofectamine RNAiMAX. Results YAP is phosphorylated by the Hippo/LATS kinase cascade at serine 127 (S127), resulting in cytoplasmic sequestration. YAP phosphorylation at tyrosine 357 (Y357) results in its nuclear localization and is Hippo/LATS independent. We first assessed the status of YAP phosphorylation in our KRAS mutant NSCLC cell lines. Among 5 KL (H460, H2030, A549, H23 and H2122) cells, 3 (H460, H2030 and A549) had higher YAP(Y357) and lower YAP(S127) expression compared to KP (H1792, SK-LU1, H2009 and Calu-6) and K-only (H358 and Calu-1) cells, normal fibroblasts (IMR-90) and the Hippo/LATS inactive breast cancer cell line, MDA-MB-231. These findings suggest the nuclear retention of YAP in KL cells. In all 3 KL cells we detected the expression of CTGF and/or Cyr61, the bona fide YAP target genes. H460 (KL) cells had the highest PD-L1 expression, although high PD-L1 expression was also seen in KP (H2009) and K-only (Calu-1) cells. Then we sought to explore whether YAP serves a functional role in KL cells compared to KP or K-only cells. H460 (KL), H1792 (KP), and H358 (K-only) cells were transfected with YAP siRNA or control siRNA. YAP protein expression was reduced in all cells by 70-90% compared to control siRNA-transfected cells. Transfection with YAP siRNA reduced the viability of H460 (KL) cells more profoundly compared to H1792 (KP), and H358 (K-only) cells. The effect of YAP silencing on downstream signaling and immune cell composition and the co-targeting of YAP and MEK in vitro and in vivo are ongoing. Conclusions STK11/LKB1 alterations have been identified as a major driver of primary resistance to PD-1 or PD-L1 blockade in KRAS mutant NSCLC. YAP acts as a transcriptional driver of cytokines that orchestrate the immunosuppressive microenvironment within KRAS mutant tumors. Our results corroborate the role of YAP in KRAS mutant NSCLC and allow considering the synthetic lethality of YAP suppression with MEK inhibitors or immunotherapy as a promising strategy to enhance treatment response and patient survival. Citation Format: Marina Keil, Richard Schneider, Elisabeth Trivier, Christian Dillon, Dirk Wienke, Anita Seshire, Linda Pudelko, Andree Blaukat, Niki Karachaliou. The role of YAP signaling in KRAS driven non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5916." @default.
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• W3082880931 date "2020-08-13" @default.
• W3082880931 modified "2023-10-17" @default.
• W3082880931 title "Abstract 5916: The role of YAP signaling in KRAS driven non-small cell lung cancer" @default.
• W3082880931 doi "https://doi.org/10.1158/1538-7445.am2020-5916" @default.
• W3082880931 hasPublicationYear "2020" @default.
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